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Microbiol Mol Biol Rev. Mar 2003; 67(1): 86–156.
PMCID: PMC150520

Bacteriophage T4 Genome

Abstract

Phage T4 has provided countless contributions to the paradigms of genetics and biochemistry. Its complete genome sequence of 168,903 bp encodes about 300 gene products. T4 biology and its genomic sequence provide the best-understood model for modern functional genomics and proteomics. Variations on gene expression, including overlapping genes, internal translation initiation, spliced genes, translational bypassing, and RNA processing, alert us to the caveats of purely computational methods. The T4 transcriptional pattern reflects its dependence on the host RNA polymerase and the use of phage-encoded proteins that sequentially modify RNA polymerase; transcriptional activator proteins, a phage sigma factor, anti-sigma, and sigma decoy proteins also act to specify early, middle, and late promoter recognition. Posttranscriptional controls by T4 provide excellent systems for the study of RNA-dependent processes, particularly at the structural level. The redundancy of DNA replication and recombination systems of T4 reveals how phage and other genomes are stably replicated and repaired in different environments, providing insight into genome evolution and adaptations to new hosts and growth environments. Moreover, genomic sequence analysis has provided new insights into tail fiber variation, lysis, gene duplications, and membrane localization of proteins, while high-resolution structural determination of the “cell-puncturing device,” combined with the three-dimensional image reconstruction of the baseplate, has revealed the mechanism of penetration during infection. Despite these advances, nearly 130 potential T4 genes remain uncharacterized. Current phage-sequencing initiatives are now revealing the similarities and differences among members of the T4 family, including those that infect bacteria other than Escherichia coli. T4 functional genomics will aid in the interpretation of these newly sequenced T4-related genomes and in broadening our understanding of the complex evolution and ecology of phages—the most abundant and among the most ancient biological entities on Earth.

T4 GENES TO GENOME

T-even phages (Fig. (Fig.1)1) have been major model systems in the development of modern genetics and molecular biology since the 1940s; many investigators have taken advantage of their useful degree of complexity and the ability to derive detailed genetic and physiological information with relatively simple experiments. Bacteriophages T2 and T4 were instrumental in the first formulations of many fundamental biological concepts. These include the unambiguous recognition of nucleic acids as the genetic material; the definition of the gene by fine-structure mutational, recombinational, and functional analyses; the demonstration that the genetic code is triplet; the discovery of mRNA; the importance of recombination in DNA replication; light-dependent and light-independent DNA repair mechanisms; restriction and modification of DNA; self-splicing introns in prokaryotes; translational bypassing; and others (506, 697). The advantages of T4 as a model system stemmed in part from the virus's total inhibition of host gene expression, which allows investigators to differentiate between host and phage macromolecular syntheses. Analysis of the assembly of the intricate T4 capsid and of the functioning of its nucleotide-synthesizing complex, its replisome, and its recombination complexes has led to important insights into macromolecular interactions, substrate channeling, and cooperation between phage and host proteins within such complexes. Indeed, the current view of biological “molecular machines” (15, 16) has its beginnings in T4 biology; the T4 replisome, late gene transcription complex and capsid assembly are paradigms of molecular machines.

FIG. 1.
Electron micrographs of bacteriophage T4. The well-recognized T4 morphology was nature's prototype of the NASA lunar excursion module. (A) Extended tail fibers recognize the bacterial envelope, and its prolate icosahedral head contains the 168,903-bp ...

The redundancies of protein functions and of pathways of DNA transactions probably allow T-even phages to exploit a broad range of potential hosts and environments while conferring substantial resistance against a wide range of antiviral mechanisms imposed by the host (4a, 599, 599a, 601, 786). T4 also produces several enzymes with widespread commercial applications, including its DNA and RNA ligase, polynucleotide kinase, and DNA polymerase. Many would argue that to know T4 is to know the foundations of molecular biology and the essential paradigms of genetics and gene expression.

There was a price to pay for all of the benefits provided by this highly tractable genetic system. Early efforts to clone T4 genes were largely thwarted by the glucosylated hydroxymethyl cytosine (HMC) DNA (which is central to the high expression and replication of the phage genome, the concurrent total inhibition of host transcription, and the eventual degradation of the host DNA). Most of the available restriction endonucleases failed to digest T4 DNA, delaying the gene-by-gene cloning analysis that rapidly advanced in other model organisms. Eventually, multiply mutant T4 strains defective in the nucleases that cleave unmodified DNA, in the enzymes leading to the synthesis of HMC-DNA, and in the protein blocking transcription of cytosine-containing DNA were constructed (1020). These T4dC (or T4C) strains permitted the construction of detailed restriction maps of T4 (137a, 139, 600, 814, 833a, 1214) and rapidly accelerated cloning and sequence analysis of T4 gene clusters. By the early 1990s, much of the genome had been sequenced, but extensive regions remained intractable. The uncloned DNA appeared to largely encode proteins involved in the transition from host to phage metabolism, nucleases, and other proteins toxic to the Escherichia coli cloning host. These regions were sequenced by different members of the T4 community, who closed the gaps by using PCR to carry out direct sequencing without cloning. Regions that have not otherwise been published include the nrdC-tk region (laboratory of E. Kutter), the e-tRNA region (laboratories of V. Mesyanzhinov and E. Kutter), the 34-35 region (laboratory of E. Goldberg), the t-asiA.5 region (laboratory of J. Drake) and the ndd-rIIB region (laboratories of K. Kreuzer and M. Uzan). The complete 168,903-bp sequence of the T4 genome is available as GenBank accession no. AF158101 and as entry NC_000866 at the NCBI Entrez Genome site (http://www.ncbi.nlm.nih.gov/Entrez). Among sequenced viruses in the database, only Pseudomonas phage [var phi]KZ (727), the African swine fever virus, herpesviruses, chlorella virus, and vaccinia virus have larger genomes.

The T4 genome is a rich arena for evaluating complete genomes in the context of a well-characterized biological system. Here, we demonstrate the use of some of the computational tools currently available for complete genome sequence analysis and discuss the new insights gained from this analysis of the T4 genome and its nearly 300 genes.

NUCLEOTIDE SKEW IN THE T4 GENOME

T4 DNA has only 34.5% G+C, while its E. coli host has about 50% G+C. If T4 were assembled from “modules” of other genomes, as has been suggested for many phages (discussed below), different regions might be expected to have quite different G+C contents, particularly if they were recently acquired. However, only 18 of the known or predicted genes have less than 60% A+T and only 4 have less than 58%. Therefore, while some genes may have been more recently acquired, most of the T4 genome appears to have a lengthy, common history. Interestingly, it is the capsid proteins that have the lowest A+T contents, and these are the most widely conserved in the T4-related phages (701, 748, 919, 1069) and presumably among the earliest to have arisen. Gene 23, encoding the major head protein, is the lowest, at 55% A+T. It also uses the highest proportion of codons that are translationally optimal for the host (65%), in keeping with its very high level of expression; about 1,000 copies of the protein are needed per phage particle synthesized.

A substantial skew toward G and against C in the coding strand is observed in translated regions. Only four genes have more than 20% C in the coding strand, while about 130 have more than 20% G and 37 have more than 22% G. A and T are more equitably divided between the strands. However, the AT bias is strong in the third position of codons, as expected with high-A+T genomes, and reflection points in the bias (Fig. (Fig.2)2) do correlate with changes in the direction of T4 transcription (499). Whether these biases are coupled to effects of transcription or replication on directional mutation pressure, as suggested previously (499), remains to be demonstrated. Variably used multiple origins of T4 DNA replication (see below) presumably preclude the use of nucleotide skew analysis to identify the origin of replication, as it is often used for microbial chromosomes (352). Overall, AT skew is a strong predictor of T4 coding regions and the transcribed strand, although in a few regions both strands are transcribed and, in at least one region, both are translated.

FIG. 2.
Intrastrand biases (nucleotide skew) in the T4 genome. (A) Cumulative values of the number of T's minus the number of A's in a contiguous strand of the T4 genome for the first (•), second (□), and third (○) codon positions and ...

A genome of AT compositional bias presents issues of DNA structure that are worthy of brief consideration. Starting with a balanced 50% A+T genome, each GC replaced by an AT base pair eliminates one Watson-Crick hydrogen bond. This suggests that the evolution of HMC and glucosylation conferred a secondary selective advantage: it not only protects the DNA against degrading endonucleases but also improves double-strand stability. The OH and H side groups of the added glucose are able to form hydrogen bonds when in proximity with neighboring bases (456, 457). With only one hydrogen bond formed per glucose residue, the approximately 16% glucosylated HMC in T4 DNA could compensate for the 14% A+T bias above average in the genome.

The AT-rich T4 genome may also present features advantageous for a virus: a DNA structure different from the B-DNA of its host (809). On a local scale, the structure would approach D-form DNA: a polymer consisting of poly(dA-dT) double strands, overwound with only 8 bp per turn, a wider and shallower major groove, and a deeper and narrower minor groove (126, 127, 636). Close contacts of the glucosyl residues with side groups of neighboring bases could alter the preferred values of roll, slide, and twist angles of base pairs (258). Such forces and structural features can influence the outward appearance of the DNA in a way that may be recognized by proteins. Enzymes that melt DNA as part of their action (such as RNA polymerase and DNA polymerase) might transcribe and replicate AT-rich DNA faster than they would transcribe and replicate DNA with a balanced GC and AT content or might attract RNA polymerase and other host proteins in a competitive manner.

IDENTIFYING T4 GENES

On the basis of all available criteria, we conclude that T4 has about 300 probable genes packed into its 168,903-bp genome. The nucleotide positions of all probable genes, promoters, terminators, and the best characterized origins of replication are given in Table Table1,1, along with several calculated properties for the genes and their encoded proteins. T4 has a total of 289 probable protein-encoding genes, 8 tRNA genes, and at least 2 other genes that encode small, stable RNAs of unknown function. Table Table22 summarizes and references the functions and properties of the approximately 156 genes that have been characterized by mutation and/or by the properties of cloned gene products. Imprecision in the number of “genes” reflects ambiguities of genetic nomenclature, when some genes contain multiple coding regions (for instance, genes 16, 17, and 49 encode more than one protein).

TABLE 1.
Feature coordinates of the T4 genome
TABLE 2.
Functions and mutant phenotypes of T4 gene products

Computational Strategies for Gene Assignment

The probability that an open reading frame (ORF) encodes a protein can be estimated by various computational methods that depend on observed patterns in the distribution of bases in known genes, along with such criteria as the presence of apparent translation initiation regions and the relationship to promoters and other genes. In the assembly and annotation of the T4 genome, the main tools used were the correlation coefficient, which compares the fractional use of each base at each of the three codon positions to those of a set of known T4 genes (971; T. Stidham, S. Peterson, and E. Kutler, Abstr. Evergreen Int. Phage Biol. Meet. p. 51, 1993), and the linguistics-based analysis, GenMark (99, 671). These methods were supplemented by identification of likely Shine-Dalgarno (SD) sequences for ribosome binding. As discussed below, such analyses indicate that virtually all the uncharacterized ORFs of T4 probably do encode proteins. Most known T4 genes have correlation coefficients above 0.85, as do most of the unassigned ORFs (Table (Table1).1). However, there appear to be constraints on the composition of some specific proteins that result in far lower values. This is seen for a few of the well-characterized but very small T4 genes, such as stp (−0.14), and for those that are predicted to encode integral membrane proteins, such as imm (0.31) and ac (0.51). Negative values are generally seen where a short but definitely expressed reading frame is superimposed on a different reading frame of another gene, such as 30.3′, or in the complementary strand, as in repEA and repEB. Therefore, while a high correlation coefficient makes it very likely that an ORF does indeed encode a protein product, a low correlation coefficient cannot be used to exclude that possibility.

Work with T4 makes it clear that precisely identifying protein-coding regions can be complex, even in prokaryotes. (i) Five known T4 genes and several other ORFs have functional internal starts, with good experimental evidence for genes 17 and 49 that the shorter proteins have distinct functional roles (39, 286, 784, 788). In these two cases, separate but related gene names have been assigned (e.g., 17, 17′, and 17") to indicate this complex relationship. We expect that other examples of internal translational start sites will be identified.

(ii) Five other genes and ORFs have two closely spaced start codons with similarly strong values for the sequence information content (defined below) at their translation initiation sites (or ribosome binding sites [RBS]). These include alc, vs.4, e.5, tRNA.2, and 57B. Until further evidence is available, we have listed these genes as simply starting from the first of the two possible sites. It will be interesting to determine if both starts are used in any or all of these cases and if there are special functions for two nearly identical proteins. In bacteriophage lambda, for example, two nested proteins, differing in start sites by only two amino acids, have important complementary functions: one makes the pore to permit access by lysozyme to the peptidoglycan layer, and the other delays formation of the pore (91). The regulation of the balance between these two genes is not understood but is crucial in determining the timing of lysis.

(iii) It is clear that there can be genes within genes in different reading frames. These can be read in the same direction, as seen for gene 30.3′ (1234). They can also be in the opposite orientation, as seen for genes repEA and repEB, which are associated with initiation from origin E and are located opposite gene 5 (1109).

(iv) Introns that are later spliced out of the transcripts occur in at least three T4 genes: the thymidylate synthase gene (td), the gene encoding a subunit of the aerobic ribonucleotide reductase (nrdB), and the anaerobic ribonucleotide reductase gene (nrdD) (615, 991, 1229).

(v) As first demonstrated in T4 gene 60, an unusual relationship between nucleic acid and protein sequence can also occur through translational bypassing. A 50-base mRNA segment in the coding region is not translated in gene 60 by a mechanism that depends on cis-acting signals in the mRNA, ribosomal protein L9, a pair of GGA codons 47 bases apart, and the structure of the cognate glycyl tRNA (408, 450). This is the only known high-efficiency bypass site; to date, the phenomenon is unique to T4. Bypass with much lower efficiency appears to occur at the junction of genes 56 and 69 (segF) (160, G. Mosig, unpublished data).

Programmed frameshifting, which shifts translation by 1 base into the +1 or −1 reading frame, can expand the coding capacity of a genome (13). To date, no instance of programmed frameshifting has been identified in T4, although many other viral DNA and RNA genomes use this approach to “recode” (322).

T4 shows nearly four times the gene density predicted for herpesviruses and yeast and twice that for E. coli (92, 556, 557). The high gene density reflects both the small size of many T4 genes and the fact that there are very few noncoding regions (about 9 kb, 5.3% of the genome). Furthermore, regulatory regions are compact, occasionally overlapping coding regions. In many cases, the termination codon of one gene overlaps the start codon of the next gene (see “Translation and posttranscriptional control” below). In addition, T4 has several groups of nested genes as mentioned above. Clearly, computational and bioinformatic tools do not yet identify all the genes and complex coding arrangements in a genome perceived by many to be “simple,” like that of T4.

Table Table33 summarizes the functional assignments of T4 genes, referring to the color codes used in the functional genome map of Fig. Fig.3.3. Some T4 proteins have multiple activities and are listed in more than one group. For example, T4 RNA ligase A (rnlA or 63) is also a catalyst for attaching tail fibers. Alternatively, a single activity can be viewed as being involved in multiple processes. For example, the nucleases EndoII and EndoIV (encoded by denA and denB) are responsible primarily for initiating degradation of cytosine-containing host DNA. They are included in the “nucleotide precursor” category because one important function of these proteins is the timely provision of nucleotide precursors. They are also included among the host alteration/shutoff genes.

FIG. 3.
Functional genome map of bacteriophage T4. The coding capacity of the T4 genome is shown for both characterized and hypothetical ORFs. The color scheme (by gene function) is as defined in Table Table3.3. Origins of DNA replication (ori) indicated ...
TABLE 3.
Functional categories of T4 genesa

Characterized T4 Genes and the Early Genetics

Only 62 of the T4 genes are “essential” under standard laboratory conditions (rich medium, aeration, 30 to 37°C); mutants altered in a few other genes produce very small plaques under standard conditions. Many of these key genes are much larger than the average T4 gene; together, they occupy almost half of the genome. They include genes that encode proteins of the replisome and of the nucleotide-precursor complex, several transcriptional regulatory factors, and most of the structural and assembly proteins of the phage particle. Most of these genes were first identified by the isolation of amber or temperature-sensitive conditional-lethal mutations and were assigned numbers (Table (Table2)2) before their functions were determined (264).

Nonessential genes were typically assigned letter designations, reflecting the phenotype associated with the mutation (Table (Table2)2) or the host function that the gene duplicated (nrd, frd, td, etc.). They encode such products as enzymes for nucleotide biosynthesis, recombination, and DNA repair; nucleases to degrade cytosine-containing DNA; proteins responsible for exclusion of superinfecting phage, for lysis inhibition under conditions of high phage/host ratios, and for other membrane changes; and inhibitors of host replication, transcription, and protease activity. Unfortunately, the designation by letters versus numbers does not automatically identify a gene as essential. For example, the products of genes t, motA and asiA are essential under standard conditions, while that of 69 (segF) is not. Mutations in genes 46 and 47 still permit the synthesis of a few phage per cell, but too few are produced to reliably produce plaques under most conditions; a burst size of about 10 is generally required for plaque formation. Primase (gene 61) and topoisomerase (genes 39, 52, and 60) mutants produce plaques at temperatures above 25°C because they can use a recombinational bypass mechanism to prime lagging-strand DNA synthesis (784, 788). In several cases, mutations initially assigned to different genes by spot-test complementation ultimately proved to reside within the same gene; thus, genes 58 and 61 are identical, as are genes 2 and 64 and genes 4, 50, and 65.

Most genes first identified by mutation have now been located in the DNA sequence. However, no genes have yet been identified for any of the reported ribosome-binding proteins or other proteins that might be involved in the shutoff of host translation (reviewed in reference 1166). Mutations ama, stI, stIII, rs, goFB, and goFC have not been assigned to a sequence; the original mutants identifying most of these genes have been lost.

ORFs of Unknown Function and Host Lethality

As noted above, the T4 genome is tightly packed with probable genes. Almost half of these still do not have an assigned function, but most have some or many of the characteristics of true T4 genes that encode known proteins. By convention among T4 researchers, each hypothetical or uncharacterized ORF is named sequentially in the clockwise direction by reference to the preceeding known gene, as in “xxxY.n”. Therefore, dexA.1 and dexA.2 are the two ORFs following dexA on the map. This convention immediately locates each such ORF on the T4 map but implies nothing about its function. The only exceptions to this convention are in positions where an ORF follows a gene transcribed in the opposite direction or with very different timing. In those cases, the ORF may be rooted to the following gene on the map, but a minus sign is used (e.g., uvsY.−1, rI.−1).

Most of the 127 uncharacterized ORFs lie in regions transcribed counterclockwise from strong early promoters. Only 16 of the uncharacterized ORFs would be expressed late in the T4 infection cycle. These are (i) ORFs under control of a late promoter in the clockwise direction, where almost exclusively late genes are found (5.1, 5.3, 5.4); (ii) ORFs following late promoters (some of which also may still be expressed from upstream early and/or middle promoters) in the counterclockwise direction (rI.1 and rI.−1; 24.2 and 24.3; uvsY.−1 and uvsY.−2; alt.−1 to alt.−3; and 30.9); and (iii) ORFs following middle promoters and without late promoters (denB.1)

Because they are likely to be expressed immediately after infection, some of the 127 uncharacterized T4 ORFs may be involved in the transition from host to phage metabolism or in resistance to plasmid- or prophage-encoded toxic proteins. Many of these genes (shown in white in Fig. Fig.3)3) are in regions that can be deleted without seriously affecting phage production under usual laboratory conditions. However, at the same time, they have largely been retained in T4-related phages (534, 596, 919; E. Kutter et al., unpublished data about the nrdC-tRNA region). Most of the T4 early promoters are in these widely conserved yet deletable regions, which are densely packed with the predicted ORFs. Many of the hypothetical ORF proteins—at least those over about 9 kDa—have been identified on two-dimensional gels by comparing labeled proteins produced by wild-type and the T4 deletion strains (604). These proteins are often produced in large quantities just after infection. Those that have been tested are generally lethal or very deleterious to the growth of E. coli.

Together, these findings suggest that the host-lethal, immediate-early proteins confer selective advantage for the phage but that they are necessary only under certain environmental conditions, for infecting other hosts, or that there is redundancy in their functions. Some of the proteins are quite large, but most are smaller than 15 kDa. In general, work with T-even phages emphasizes that small hypothetical ORF-encoded proteins should not be overlooked. The smallest characterized T4 protein, Stp, consists of only 29 amino acids; 62 predicted T4 proteins have fewer than 100 amino acids.

Most of the unidentified ORFs show very little homology to non-phage genes in the databases. That many of these ORFs are deleterious to E. coli when cloned reinforces the notion that their products inhibit or redirect important host proteins and that they may be useful in studying cellular proteins in their active, functional state. One example, the Alc protein, specifically terminates the elongation of transcription on cytosine-containing DNA (599, 601). Alc appears to uniquely recognize the rapidly elongating form of the RNA polymerase (RNAP) complex. It would be a valuable tool for studying the dynamic structural changes that occur in the polymerase during transcription; all other current approaches only examine the polymerase paused at particular sites and infer its behavior from the resultant static state.

Some of the host-lethal proteins may also suggest new targets for antibiotics. They should also aid in studies of evolutionary relationships and protein-protein interactions.

Another interesting set of proteins involved in the transition from host to phage gene expression involves three different ADP-ribosyltransferases. These include Alt, which is packaged in the phage particle and carried into the cell with the DNA, ModA, and ModB. The role of these ADP-ribosylation activities in the T4 transcription cycle is detailed below.

To fully understand the takeover of host metabolism by T4-like phages, it will be necessary to identify the ORFs that indeed encode proteins in vivo and to determine their biological functions and the conditions under which they exert their effects. The sequences of some of the small proteins that have been studied are highly conserved among the T-even phages, presumably reflecting their complex interactions with multiple cell components.

PROMOTERS AND TRANSCRIPTION FUNCTIONS

T4 transcription uses three major classes of promoters—early (Pe), middle (Pm), and late (Pl)—which broadly define the developmental stages of the T4 infection cycle (Fig. (Fig.4).4). The genomic positions of these promoters and of rho-independent terminators are indicated in Table Table1.1. The overall temporal pattern of transcription through the T4 genome is quite complex. Many genes are served by multiple classes of promoters, and so a number of promoters may precede genes and a terminator in a transcription unit. Furthermore, protein-dependent or cotranslation-dependent antitermination contributes to the pattern of active T4 transcripts. Some RNA processing and superimposed translational controls (discussed later) also complicate the interpretation of data.

FIG. 4.
Diagram of the relationship between the T4 transcriptional pattern and the different mechanisms of DNA replication and recombination. The top panel shows the transcripts initiated from early, middle, and late promoters by sequentially modified host RNA ...

T-even phages rely entirely on the host core RNAP throughout infection. It is therefore not surprising that T4 promoter specificity and transcription are affected by the multiple interactions of the bacterial RNAP α subunits, β/β′ subunits, and σ70 promoter recognition subunit. Most studies with T4 have been done in cells growing exponentially under high aeration, where the host σ70 is present throughout infection. Under these conditions, the temporal transition through the different classes of promoters is accompanied by covalent modifications of RNAP and the appearance of new protein transcription factors that act in various ways. All of these functions serve to enhance phage promoter recognition and transcription; no DNA-binding transcriptional repressor protein has been identified in the T4 developmental cycle.

To date, little is known about T4 infection under stationary-phase or anaerobic conditions (such as the phage would encounter in nature [599a]). Preliminary evidence shows that the patterns of infection under these conditions are often very different and that the status of rpoS clearly makes a difference in the outcome of aerobic infection in stationary-phase cells (E. Kutter, unpublished data). Corbin et al. (187a) have recently shown that T4 infection affects the morphology of E. coli biofilms and that glucose-limited biofilm cells can be a reservoir for phage. Additional study of T4 gene expression under different environmental conditions is warranted.

Early Transcription

At the onset of infection, 39 T4 early promoters (plus a few host-like promoters [see below]) compete with about 650 σ70-dependent bacterial promoters for approximately 2,000 RNAP holoenzymes in the commonly studied, rapidly growing exponential cells; the polymerase number is smaller under more limiting growth conditions. T4 redirects the transcriptional machinery to T4 promoters with high efficiency, as reflected by the appearance of phage-specific proteins soon after infection, the rapid shutoff of host gene expression (reviewed in reference 599), and, ultimately, the virulence of the phage. That T4 early promoters are stronger than E. coli promoters presumably plays a major role, since most promoters can be cloned only on plasmids designed to attenuate their transcriptional activity. Transcription start sites of many of the early promoters have been mapped by primer extension off of mRNA from T4-infected cells and/or from promoter-cloning vectors (reviewed in reference 1169).

The 39 characterized Pe sequences (1168, 1169) are noted in Table Table11 and have been analyzed using the information content software developed by Schneider and Stephens (966). The sequence logos, maximizing the alignment at the −10 region and, independently, at the −35 region, are shown in Fig. Fig.5A5A (E. Miller, T. Dean, and T. Schneider, unpublished data). The analyses show that there is high conservation at the −12, −11, and −7 positions similar to that in the E. coli70 promoters. However, T4 Pe sequences have more extended −10 regions, with sequence conservation extending through the G predominating at −14 to −18. In one group of early promoters, significant conservation extends on both sides of the −10 region [5′-GTGG(TAT/CT/AAT)ACAACT-3′] up to the T at position −1 (1169). The start site of the transcript (coordinate 0 in Fig. Fig.5A)5A) is frequently an A. The Pe −35 region has a 6-bp conserved region from position −36 to −31 (GTTTAC) that differs from the E. coli -35 consensus sequence (TTGACa). Upstream of the −35 region, T4 early promoters display a bias toward A-rich tracts centered around −42 and −52 (Fig. (Fig.5A)5A) (1169). Upstream A-tract sequences (position −42) were first observed with T5 promoters (314) and have since been shown to activate certain E. coli promoters, of which the rrn operon promoters are the best studied. By affecting DNA curvature, upstream A tracts (UP elements) directly enhance Eσ70 promoter activity through interactions with the RNAP α subunit (266, 939). Many of the T4 Pe sequences include the most enhancing type of E. coli UP elements, where the two A tracts are separated by a T-rich region (266).

FIG. 5.
Logo of T4 promoters. Nearly all the sequences in each alignment have promoter activity, as demonstrated by primer extension, transcription from cloned DNA fragments, or RNA hybridization assays. The promoters included whose start sites have not been ...

Sequence logo analysis yields a quantitative parameter defined as Rsequence (Rs, which is the sequence information content of a collection of aligned sequences) (966). The sum of Rs for the −10, −35, and A-tract regions displayed for the early promoters in Fig. Fig.5A5A is 38.3 bits, which is substantially greater than the 17.6 bits (as calculated by Liebig and Rüger [639]) required to select the Pe promoters from a genome of known length and base composition (Rfrequency [see reference 966 for a thorough description of logos and information theory as applied to DNA-binding proteins]). The Rs/Rf ratio of >2 for these values suggests that the twofold excess information in the aligned T4 early promoters is due to both unmodified host RNA polymerase and its ADP-ribosylated counterpart (see below) binding and initiating transcription in these regions. The refinement of the analysis of the T4 early promoters by means of information theory is in progress (Miller et al., unpublished). Together, features of T4 early promoters allow them to be distinguished from the host promoters and elevate their transcriptional activity to a level that often exceeds that of the strongest E. coli promoters.

In addition to these early T4 promoters, there are some promoters that more closely resemble E. coli promoters. P bac (639, 1169) has been identified by mapping transcripts from cells carrying plasmid-bome T4 genes. It directs the synthesis of transcripts that are complementary to gene 3 mRNA. P repE(coordinate 79405 [Table [Table1])1]) has been identified in T4-infected cells (1109). It directs the synthesis of RepEA and RepEB proteins and an RNA primer for oriE-initiated replication. This RNA would be complementary to late-gene 5 transcripts but is undetectable by the time when these transcripts are made. Transcripts preceding gene 32 (142) have been detected that also map to σ70-like promoters. While the later are active on supercoiled plasmids, little to no transcription was observed in T4-infected cells. A similar promoter preceding gene 57A was inferred to be active on plasmids (409). These host-like promoters as a group may be of limited significance, when host transcription in general is turned off and RNAP is modified early during T4 infection.

T4 modifies the host RNAP in several ways after infection. However, most of these modifications are not essential to the infection process. A 70-kDa protein, gpAlt, enters the host with the infecting DNA. Alt is a mono-ADP-ribosyltransferase that targets arginine residues. It efficiently ADP-ribosylates one of the α subunits of RNAP in the carboxy-terminal domain at position Arg265 (323, 324, 435, 459, 937a, 1011) and ADP-ribosylates the three other polymerase subunits to a lesser extent, along with a number of other uncharacterized polypeptides. ADP-ribosylation of RNAP by cloned Alt protein leads to enhanced transcription from cloned T4 early promoters (544). Mutation analyses reveal that T4 early promoters interact strongly with unmodified RNAP and even better, in most cases, with RNAP in which only one of the α subunits is ADP-ribosylated. In particular, base position −33 of the T4 promoter and the A-rich UP element at position −42 contribute to the strong interactions with ADP-ribosylated RNAP of T4-infected cells (1026). Therefore, Alt presumably contributes to the preferential transcription from T4 promoters after infection (1168, 1170).

Shortly after infection, two new ADP-ribosyltransferases are expressed, ModA (23 kDa) and ModB (24 kDa) (780, 1077). ModA, first observed by Skorko et al. (1011), ADP-ribosylates the α subunits of host RNAP but shows no activity toward the β, β′, and σ subunits. Like Alt, ModA ADP-ribosylates Arg265 on the α subunit; unlike Alt, it targets both α subunits, not just one. ADP-ribosylation replaces the positive charge of the Arg residue by two negative charges carried by the two phosphate groups and affects DNA-protein as well as protein-protein interactions. This second ADP-ribosylation inhibits transcription from promoters with the UP element; expression of cloned modA is highly lethal to the host. (The action of ModB [205] is summarized below.)

Middle Transcription

Thirty T4 middle promoters (Pm) were compiled and are presented in the sequence logo of Fig. Fig.5B.5B. All of the middle promoters used in the logo have been mapped with respect to the 5′ end of the transcript and shown to be dependent on the transcriptional activator protein MotA (reviewed in references 692, 987, and 1043). There appears to be little dependence on an A at the +1 start site of the middle transcripts (coordinate 0 in Fig. Fig.5B).5B). The conserved −10 region resembles that of the Pe sequences (5′-TATAAT-3′ is most common), with −12, −11, −8, and −7 having nearly the same base composition. As seen for T4 early promoters, sequence conservation extends into the traditional spacer region of Eσ70 promoters, up to position −16. Significantly though, T4 Pm sequences have neither the well-characterized Eσ70 −35 region nor the Pe −35 region. Middle promoters are characterized by a specific −30 sequence called the Mot box, which extends between −32 and −27, with GCTT being the most highly conserved. The information content (Rs) calculated for the optimally aligned regions from −60 to +10 of the logo in Fig. Fig.5B5B is 21.1 bits, with 13.1 bits of the information being associated with the −10 alignment. This is considerably less than the 38-bit Rs value of the Pe promoters, implying that there is less competition with host promoters for RNAP, perhaps because host DNA is already being degraded and ADP-ribosylation of RNAP is completed. Approximately 8 bits of Rs information are required for MotA to recognize the MotA box sequence. T4 middle promoters are all located on the minus strand (Table (Table1)1) relative to the GenBank genome entry. Fourteen new middle promoters have been recently described (1095a; R. Nivinskas, personal communication).

T4 gene products AsiA and MotA are required for middle-mode transcription. AsiA is an anti-σ factor protein (see reference 454a for a review of anti-σ proteins) that coactivates RNAP for middle-mode transcription initiation by the formation of AsiA-σ70 heterodimers (12, 180, 1104). This interaction interferes with the recognition of −35 promoter sequences and at the same time stimulates T4 middle-mode transcription (180, 425, 1103, 1104). The AsiA-σ70 interaction is regarded as the pivotal event in the transition between T4 early and middle transcription: in vitro it both inhibits the recognition of most host promoters and early T4 promoters and stimulates T4 middle-mode transcription (180, 425, 848, 849, 1104). However, in vivo, defective asiA mutants do not prolong early transcription (858), suggesting that other proteins (i.e., ModA and ModB) turn off most early T4 promoters. MotA is a DNA-binding transcriptional activator protein that binds to the MotA box sequence (Fig. (Fig.5B)5B) through its C-terminal domain, facilitating Pm promoter recognition and transcriptional activation (see the model proposed in reference 987 and in Fig. Fig.44 of that reference). MotA and AsiA together increase the initial recruitment of RNA polymerase to T4 middle promoters and facilitate the clearance of RNAP from the promoter and into the elongation mode (419).

Late Transcription

Late transcription is responsible for the synthesis of T4 head, tail, and fiber proteins, in addition to the several virion assembly factors (1173) and recombination genes required for T4 late recombination/replication (784) (see below). Fifty late promoters (Pl) have been compiled and aligned for the Pl sequence logo shown in Fig. Fig.5C.5C. There is only a slight bias toward purines at the +1 transcription start site, while there is extensive conservation of the −10 sequence TATAAATA from −13 to −6. This sequence alone contributes the major information content for late promoters, which have an Rs value (see the definition above) of 16.2 bits. There is no −35 or MotA-like −30 sequence in T4 late promoters. T4 encodes one of the smallest known sigma factors, gp55 or σ55, for RNAP recognition of late promoters (1173). It specifically recognizes the −10 region sequence. Although σ55 is required to selectively initiate transcription at T4 late promoters, it is not sufficient. AsiA does not appear to be a major determinant of middle- versus late-promoter competition (552). Instead, another phage-encoded protein, gp33, acts as a coactivator of late transcription, mediating interactions between σ55 and the sliding clamp encoded by T4 gene 45. The trimeric gp45 protein is a key component in the processivity of the DNA replication complex and is also essential for late transcription (a “mobile enhancer” [405, 1186]). Primer-template junctions and single-stranded DNA (ssDNA) nicks are the most efficient loading sites for gp45, which is loaded by the clamp-loader proteins gp44 and gp62; gp45 slides on the DNA, enhancing the opening of late promoters more than 1,000 bp away from the loading site. Activated late promoters outcompete middle promoters on the same plasmid in vitro, especially at higher ionic strengths. This advantage is enhanced by ADP-ribosylation of RNAP α subunits and by binding of the phage-encoded RpbA protein to the RNAP core (552, 1082, 1173). DsbA protein is thought to also affect transcription from some late promoters (995), although it is not essential (1114).

At least three T4 proteins—Mrh, Srd, and Srh—are implicated in the interactions of different host sigma factors with core RNAP (781). Under heat shock conditions, the host σ32 (RpoH) competes with other sigma factors for host core RNAP (354, 482). The products of the two nonessential genes mrh and srh together modulate the phosphorylation of σ32 using ATP (781; Mosig, unpublished). Presumably, this would be most important for T4 late transcription, since T4 σ55 is one of the weakest known sigma factors. Consistent with this idea, infection with wild-type T4 of one specific host rpoH mutant (but not others) is aborted at the onset of late transcription, unless the T4 mrh gene is deleted (290). Srh protein resembles a segment of σ32 that interacts with RNAP, suggesting that it acts as a decoy. Similarly, T4 Srd protein resembles an RNAP-interacting segment of σ70 and σ38 (RpoS; stationary-phase and oxidative stress sigma factor) and would also decoy RNAP from the host promoters. Expression of srd from a clone is lethal to E. coli.

Microarray Analysis of T4 Transcription

In a recent report (672), the expression profile of the entire T4 genome was evaluated by mRNA hybridization microarray analysis. RNA samples were obtained from 0 to 25 min during a T4 infection cycle at 30°C. Gene expression patterns were then evaluated by cluster analysis. Early-, middle-, and late-gene clusters were clearly identified and were in striking agreement with the extensive literature for individual T4 genes. Exceptions were in regions yielding overlapping transcripts from different promoters, where temporal assignments would be more difficult. Of particular note was the complete absence of late-gene expression prior to 15 min, with the near cessation of all early- and middle-gene transcription following onset of the late period. The analysis, as stated by the authors, not only confirms the extensive literature on T4 but also suggests that microarray-based expression profiling will be a valuable tool in determining the transcription pattern, and ultimately the function, of the hypothetical and uncharacterized T4 genes. Similar strategies will be invaluable for future studies of other phage and viral genomes.

Transcription Termination and Predicted RNA Structures

Intrinsic transcription terminators.

Intrinsic, Rho-independent transcription termination sites are characterized by an intramolecular RNA helix (stem-loop or hairpin) in the mRNA, followed by a U-rich sequence (33, 364, 929, 1209). These features were used in the computer programs TransTerm, GCG Terminator, and FindPatterns (211, 265) to predict probable Rho-independent terminators in the T4 genome (E. Miller, unpublished data). About 15 years ago, 4-nucleotide UUCG loop sequences were characterized in T4 as conferring exceptional stability to RNA secondary structures (1100). Following that initial report, other stabilizing RNA tetraloop sequences were described (412, 1183), and their prevalences in E. coli Rho-independent terminators were later compiled (201). Identification of T4 transcription terminators was enhanced using pattern searches for the prominent tetraloop sequences (e.g., UUCG and GNRA), which to date are not included in the TransTerm or Terminator search parameters. In some cases, the predicted RNA structures may act to stabilize mRNA against degradation rather than functioning directly in termination (142, 340).

Features of the predicted intrinsic transcription terminators in the T4 genome are summarized in Table Table4,4, and their genome positions are noted in Table Table1.1. Overall, 34 terminators were located between genes or at the 3′ end of an ORF; 24 of these are predicted to be on early transcripts (therefore, their sequence corresponds to the minus strand of the T4 GenBank entry), while 10 are on late transcripts. The predominant tetraloop sequence is UUCG, found in 18 of these terminators, while 3 are GAAA and 3 are GCAA. All are about equally present on early and late transcripts. The remaining 10 transcription terminators have noncanonical 4-nucleotide loop sequences or have 3-, 5- or 6-base loop regions. Their features and locations suggest that they, too, are probably functional.

TABLE 4.
Intrinsic terminators mapped or predicted on the T4 genome

Many of the probable terminators are located at the ends of long early or middle transcripts, preceding a downstream early or middle promoter. Among these early (or prereplicative) transcription terminators, there are several instances where the 3′ U-rich region of the terminator is a sequence shared with an A-rich UP element for a distal early promoter (see above) (1169). In several instances (such as positions 108613 [between 24 and 24.1], 122720 [between 54 and alt.-3], 114472 [between uvsW and uvsY.-2], and 160924 [between asiA and t]), a terminator is located at the 3′ end of one of two adjacent genes transcribed in opposing directions. There is always an intrinsic terminator at the end of a late gene region that otherwise would be transcribed into a prereplicative region on the opposite strand (such as positions 106537, 108613, 122720, and 160924). However, the presence of intrinsic terminators at the ends of early transcripts that enter late regions is not as consistent. At some early-late junctions (e.g., position 114472 [ORF uvsY-.2 3′ end]), a terminator is predicted and experimentally identified (356, 357). At other junctions, no prereplicative intrinsic terminator is predicted (see position ca. 160875 [asiA 3′ end]) or, if a nearby terminator is indeed the transcript end, there would be ORFs that are not served by an apparent promoter. An example of the latter is position 110180 (hoc 3′ end), which orphans rnlB, 24.2, and 24.3 without a promoter, except as available from readthrough transcription.

Seven regions were identified by the programs described in the preceding section as possible transcription termination sites, although they showed unusual attributes with respect to their location and the 3′ U-rich region. Some are located wholly within coding regions (e.g., position 81769).

Overall, the predicted T4 intrinsic terminators generally appear to both define the 3′ ends of multicistronic mRNAs and affect the dynamics of transcription complexes advancing on opposing DNA strands.

Rho-dependent transcription terminators.

In enteric bacteria, the RNA-binding protein Rho modulates transcription termination at sites that are distinguished from intrinsic terminators by the absence of both the stable RNA hairpin and the 3′ U-rich region. Rho utilization sequences (rut) in RNA generally are C-rich, have small amounts of G, and can be as long as 85 nucleotides (929). In addition, rut sites can be 150 to 200 bp 5′ of the actual transcription termination site and therefore appear to function as locations for entry of Rho on transcribed RNA. Some of the better studied Rho-dependent termination sites (i.e., lambda tR1 and E. coli tnp) are regulated by antitermination which also involves host Nus proteins, lambda N protein, and the RNA sequence of the boxA and boxB regions (344, 553, 929). Together, these complex features have made computational methods for identifying Rho-dependent termination sites problematic relative to the easily defined intrinsic terminators.

Rho-dependent transcription termination sites in T4 have not been extensively characterized; little additional work has been done since the review by Stitt and Hinton (1043). One of the better candidate Rho terminators, or a 3′ end of the RNA that is indirectly influenced by a rho mutation, lies between genes uvsX and 40 (416). Readthrough transcription from uvsX into 40 (and on through the helicase gene 41) is diminished by the Rho mutant rho026 (1044). In addition, the low level of readthrough transcripts is elevated in goF (comCα) mutants, probably by better protection against RNases (416, 1043). The Rop protein of ColE1-derived plasmids has a stabilizing effect similar to that of goF mutations (1028). As mentioned above, the uvsX-40 site (position 22347) is characterized by a stable tetraloop hairpin that is not followed by the typical U-rich sequence (Table (Table4).4). However, the rut-like C-rich region is part of a hairpin, which is not characteristic of other rut sites, and there is not an apparent nearby boxA sequence. Nonetheless, the available evidence points to this region as a likely Rho-dependent termination region. Similar properties are predicted for the putative rIIB-denB.1 terminator at position 167967. These RNA structures may help direct Rho-dependent termination.

Other sites in the T4 genome that have rut- and boxA-like sequences, and that therefore may be affected by Rho, occur at the end of the tRNA cluster (after RNA C at position 70742), in the region between genes repEB and repEA (position 78810), and between the late promoter at position 77490 and gene 5. The last two potential sites are near the oriE origin of DNA replication (1109; A. Harvey, R. Vaiskunaite, and G. Mosis, unpublished data) (see below). Other rut- and boxA-like sequences can be identified in the T4 genome, but the significance of these, as well as the entire aspect of Rho-dependent termination in the T4 developmental cycle, requires further study. Mutations in the gene goF (comCα) have been repeatedly isolated as suppressors of host mutations that affect T4 transcription termination; the GoF protein, which stabilizes residual long transcripts produced in the Rho026 mutant host, does not show overall similarity to other proteins in the genome databases (171, 956, 1043). However, the short acidic region between residues 87 and 111 is similar to amino acids in other RNA-binding proteins and ATP-dependent RNA helicases (Miller, unpublished).

TRANSLATION AND POSTTRANSCRIPTIONAL CONTROL

The transition from host to phage protein synthesis is a rapid and efficient process (601); virtually no host proteins are observed on two-dimensional gels of proteins labeled after 1 min of T4 infection (189). Intrinsic properties of T4 mRNAs, such as the strength of SD sequences, several T4-induced modifications to the translation initiation apparatus, and the translational coupling arrangement seen for many phage genes may play key roles in the shift of host ribosomes to translation of T4 mRNAs.

Ribosome-Binding Sites

In general, T4 RBS have properties that are nearly identical to those of its E. coli host (reviewed in reference 736). mRNA sequences 5′ of the initiation codon (the SD sequence) show a variable extent of complementarity to the 3′ end of 16S rRNA, followed by a spacing of 6 to 10 nucleotides and then the initiation codon. Furthermore, there is a modest bias in favor of certain codons for the second amino acid. Many T4 proteins have been purified for biochemical or structural characterization, so that their N-terminal residue and hence their translational start codon are definitively known. Where the N-terminal amino acid has not been experimentally determined, the translation initiation sites were assigned to each gene and ORF (Table (Table1)1) using predictions based on the correlation coefficient (described above), the T4 hidden Markov model (671), and the presence of an SD sequence in an appropriate position. Most of the translation start codons of T4 genes are AUG. GUG as initiator occurs at eight T4 ORFs which, at 3%, is similar to the frequency of GUG starts occurring in E. coli genes (92). T4 genes and ORFs using GUG initiation codons include mobB, dexA.2, 46, 46.1, cd.1, 55.7, 41, and 49′. One occurrence of an AUU initiation codon has been documented; it is an internal start site within gene 26 (823) (see below).

Aligned T4 RBS sequences can be collectively viewed in a sequence logo (966), although the variable spacing between the SD sequence and the AUG initiation codon presents a particular challenge. Figure Figure6A6A shows the logo aligned at the AUG. Due to the variable spacing between the SD sequence and initiation codon, only a minor peak for the SD is observed, in the −8 to −9 region. Alignment of the SD sequence alone, independent of the AUG (Fig. (Fig.6B),6B), clearly illustrates the importance of the SD sequence. The Rs (defined above) of T4 RBS sequences, using the optimally aligned regions from −15 to +14 (Fig. (Fig.6)6) is 14.3 bits, which is higher than the calculated Rs for E. coli RBS sequences (8.9 bits [994]). However, a refined “flexible” model of E. coli RBS appears to more accurately account for the variable spacing between the SD sequence and AUG (994). In effect, subtracting the uncertainty of the variable SD-AUG spacing lowers the total Rs; thus, the 14.3-bit Rs value currently calculated for T4 ribosome binding sites is likely to be slightly lower (Miller et al., unpublished). Overall, the strength of the T4 RBS would in part account for the observed redirection of ribosomes from host to phage mRNAs.

FIG. 6.
Logo of T4 RBS. Translation initiation regions of the annotated T4 GenBank file AF158101 were used; genes 25 and 38, which have extended spacing and RNA ...

A few prokaryotic “leaderless” mRNAs have been identified that lack the SD sequence and have the initiator AUG positioned right at the 5′ end of the transcript; the best-studied phage leaderless mRNA is that for the lambda cI repressor protein (833). Some leaderless mRNAs are highly expressed (e.g., aph [353, 480]). To date, no leaderless mRNAs have been characterized from T4.

The transition from host to phage protein synthesis may also involve changes that T4 reportedly makes in proteins of the translation apparatus, including IF3 alteration, release of S1 from ribosomes, and synthesis of new ribosome-binding proteins (601, 1166). These modifications to the translation initiation apparatus potentially could have major effects on the initiation efficiency of either phage or host mRNAs. Unfortunately, most of the genes responsible for these changes have not been identified. ModB ADP-ribosylates the S1 protein, elongation factor EF-TU, and the chaperone “trigger factor” (205), and thus these changes may be important for diminished translation of host mRNAs or may have a direct impact on the translation of phage mRNAs.

RNA Structure at Ribosome Binding Sites

Two T4 RBS have unusually long spacing between the SD sequence and the initiation codon, with an additional RNA helix stacked into the RNA structure of the initiating ribosome-mRNA complex. For gene 38 mRNA, an RNA helix (hairpin) in the variable SD-to-AUG spacing region brings the SD sequence from 22 bases away to within 5 bases of the AUG, which is in the range of spacing observed for other T4 genes (326, 388). Gene 25 has an SD-to-AUG spacing of 27 bases, but an intervening RNA structure reduces that to 11 bases (819). These compact intramolecular mRNA and intermolecular rRNA-mRNA helices at the RBS are reminiscent of RNA pseudoknots (428) (the regulatory RNA pseudoknot preceding the RBS of gene 32 mRNA is discussed below). T4 gene 38 and gene 25 mRNAs are good examples of how RNA structure can enhance translation initiation efficiency.

RNA structures can also have the opposite effect. Several T4 mRNAs fold into intramolecular RNA helices that inhibit ribosome binding and translation (736). Usually this is observed with mRNAs that are transcribed from early promoters and extend downstream into a late gene. The longer early transcript forms an RNA helix that sequesters the late-gene RBS (such as in the mRNAs for genes e, soc, I-TevI, and 49). Late promoters, located immediately upstream of the late-gene RBS, lack the 5′ region of the helix and present RBS sequences that are accessible for translation initiation. As mentioned below, for gene 49, the intramolecular helix at the first RBS promotes use of the internal RBS for gp49′.

Internal Initiation Sites

A few overlapping or internal reading frames have been identified in the T4 genome. In each case, the internal translation initiation sites yield proteins shortened from the amino-terminal end. T4 EndoVII (the Holliday junction resolvase), encoded by gene 49, is 157 amino acids (aa) long. An internal initiation site, utilizing a GUG start codon, yields a protein of 105 aa (39). The shorter protein is synthesized predominantly from a long early transcript in which the first RBS is sequestered in a hairpin. The larger protein is synthesized from a shorter late transcript, in which the RBS is free. The full-length T4 gene 17 product (terminase/DNA-binding protein) is 610 aa. Internal initiation sites on two shorter gene 17 mRNAs (one is initiated from an internal promoter, and the other is cleaved) yield smaller proteins of 523, 505, and 416 residues (286). Because only the largest one contains a single-stranded DNA-binding domain and the second largest one suffices to package DNA of mature size, it has been proposed that the different-sized proteins recognize different substrate DNA for recombination (288) and for packaging (784) (see below).

The rare AUU initiation codon used by gene 26′ yields a protein, initiated at codon 114, that is only 95 residues long compared to the full-length gp26, which is 208 residues long (823). The function of gp26′ is unknown.

ORF 30.3′ is the one example in T4 of a coding region that is translated in the +1 reading frame entirely within another gene (30.3). Translation of the two overlapping ORFs has been confirmed, with the internal RBS of 30.3′ resembling other T4 RBS sequences (1234).

Translational Coupling

In translational coupling, the translation initiation of a distal gene is dependent on the translation of the gene immediately upstream. The process, which has been appreciated for many years (709, 808, 846), facilitates the coordinate expression of proteins that are involved in the same metabolic pathway or that assemble into multimeric complexes. In compact, densely coding phage genomes, translationally coupled gene arrangements are commonplace, although few have been explicitly studied. Translational coupling has been examined in RNA phages (638) and ssDNA Ff phage (1230). The very first intimations of translational coupling in T4 were observed by Stahl et al. (1035). It has been specifically studied in the T4 DNA polymerase clamp loader proteins encoded by genes 44 and 62 (502, 1089, 1095); in this complex, the 44 and 62 proteins occur in a 4:1 ratio. It appears that translational coupling helps determine the relative levels of each subunit, since the frequency of translation initiation of gene 62, transmitted from the upstream translation of gene 44, was measured to be about 25% (1089). These and other genes inferred to be translationally coupled have the stop codon of the upstream reading frame close to, or even overlapping, the downstream initiation codon. In the T4 genome, there are 52 clusters of genes arranged in this fashion. Thirty-five involve only two genes. Groups with the largest number of such genes are wac-9 (five genes), cd.2-31.1 (five genes), vs-tk (six genes), and the 30.6-alt.1 region (eight genes). Many of these include ORFs of unknown function, although the translational configuration would suggest a functional relationship to the adjacent, often characterized, gene. The extent, mechanisms and significance of translational coupling in phage T4 clearly deserve further attention.

Translational Repressor Proteins

Autogenous translational repression by the T4 ssDNA-binding protein gp32 played a significant role in establishing the importance of posttranscriptional gene regulation (reviewed in references 325 and 736). T4 has three well-characterized translational repressors, gp32, gp43, and RegA. The first two proteins have high-affinity binding sites only on their own mRNAs, whereas RegA binds to several other separate mRNAs in addition to its own (736). gp32 binds to an RNA pseudoknot upstream of the RBS, which then promotes cooperative loading in the 3′ direction to block the translation initiation site (240, 428, 984). The protein is a metalloprotein that utilizes a retrovirus-like Zn(II) domain for RNA-binding specificity (363, 985). With the DNA polymerase, gp43, the repression specificity is determined by a smaller helical hairpin upstream of the RBS; binding does extend to the RBS and thereby represses translation initiation (857). T4 gp43 was the first protein used in developing the in vitro selection method (SELEX) for identifying high-affinity RNA-binding sites (1101). RegA binds and translationally represses more than a dozen T4 early mRNAs, but it does so with weaker affinity than that observed for gp32 and gp43, and the binding site is not well defined (reviewed in reference 736). One of the better T4 RegA-binding sites (Kd = 0.2 μM) overlaps the clamp loader gp44 RBS (338). This site is at an upstream RBS, with regA positioned as the most distal gene on the transcript. The configuration suggests that repression is transmitted through translational coupling to gene 62 and regA itself. SELEX-isolated binding sites did not precisely match any specific T4 site, but the consensus sequence (5′-AAAAUUGUUAUGUAA-3′) resembles many of the RegA-sensitive RBS (113). Interestingly, RegA is conserved in all T-even-related phages examined, although it is nonessential under laboratory growth conditions. Its RNA-binding domain appears to be a unique helix-loop groove structure (338, 484, 975). Structural studies of complexes bound to RNA will have to be done for all three translational repressor proteins before we can fully appreciate the details of the RNA-protein interactions.

Codon Usage

In the 275 T4 protein coding sequences, all the standard codons are used. Kunisawa (590, 591) has compared the synonymous codon usage patterns of T4 with E. coli and has found that, as expected, T4 makes greater use of codons with A and U in the third position whereas E. coli uses G or C (Table (Table5).5). The overall codon usage in T4 genes reflects the 65.5% A+T content of all coding regions and both the general base position preferences and codon biases typically observed in AT-rich genomes. E. coli tRNAs can read all T4 codons because of the wobble in third-position recognition of most codons. While T4 encodes eight tRNAs of its own (discussed below), mutants from which they are deleted grow normally in most bacterial strains and under standard laboratory conditions (5, 962, 1179).

TABLE 5.
T4 and E. coli codon usage and tRNA availability

Unrestricted use of all codon triplets requires 50% G+C and 50% A+T, whereas an AT-rich genome has an overall reduced codon capacity. This is evident from codon usage patterns. From the T4 codon usage table (Table (Table5),5), it can be calculated that T4 uses 64.7% A+T in its codons and only 35.3% G+C. These values are close to the approximate theoretical edge of 66.6% A+T to allow, by probability, for amino acids encoded predominantly by GC-rich triplets (e.g., Arg, Ala, Gly, and Pro) to be encoded only rarely. An analysis of the intrastrand bias of bases in the first, second, and third positions of codons in T4 genes has been presented by Kano-Sueoka et al. (499) and is summarized above (see “Nucleotide skew in the T4 genome”). The correlation coefficient for T4 genes (Table (Table1)1) in part utilizes the skew to predict probable coding regions for most genes—for example, over half of the G's in coding regions are found in the first position of the codon.

tRNAs

As indicated (Tables (Tables1,1, ,2,2, and and5),5), T4 encodes eight tRNAs, with the following specificities: Ile (AUA), Thr (ACA), Ser (UCA), Pro (CCA), Gly (GGA), Leu (UUA), Gln (CAA), and Arg (AGA). A prominent late transcript contains all eight tRNAs, although early and middle promoters direct transcription into the tRNA cluster as well (772). Maturation from the primary transcript occurs through the activity of host-encoded processing enzymes (962) and autocatalysis (reviewed in reference 772). In each case, the T4 tRNA recognizes a codon that is relatively minor in E. coli but more frequent in T4 genes. There is no positive correlation between the most abundant amino acids in the T4 proteome and the tRNAs encoded by the phage (591). E. coli-optimal codons are in fact used more frequently for T4 proteins present in large numbers per phage particle (such as in gp23, the major capsid protein), while T4-optimal codons, defined as those recognized by the phage tRNAs, are used more frequently for T4 proteins present in small numbers per phage particle (and probably in weakly expressed genes). This may serve to enhance the expression of low-abundance T4 late proteins, whose products are required in larger amounts than the typical low-abundance E. coli protein (590-592).

The T4 tRNAs may have been acquired more recently in the evolutionary history of the phage, possibly through the activity of the segB-encoded endonuclease located in the T4 tRNA gene cluster. Schmidt and Apirion (962) and Mosig (772) discuss how the T4 tRNAs are required in certain hosts and may help increase fitness in some environments. Phages related to T4 that have been examined also encode some tRNA genes, yet there is a surprising variation in the specific tRNAs represented (919). Additional work on the importance of the T4 tRNAs under different growth conditions, and in different hosts, would be of interest.

The program tRNAscan-SE (664) combines up to three algorithms to examine genomic sequence for putative tRNAs and pseudo-tRNAs, identifying the specific anticodon of each tRNA (http://www.genetics.wustl.edu/eddy/tRNAscan-SE/). tRNAscan-SE was used to analyze the complete T4 genome for previously undetected tRNAs, and none were found. T4 also encodes two small RNAs (RNAD and RNAC) that immediately follow the tRNA genes and are cotranscribed with them. The functions of these RNAs remain unknown.

Introns

The first intron identified in the prokaryotic world was found in the thymidylate synthase gene (td) of T4 (174). T4 has three self-splicing group I introns, one each in td, nrdB, and nrdD (sunY) (reviewed in reference 992); the last two genes encode subunits of the aerobic and anaerobic ribonucleotide reductases, respectively. All three introns are structurally similar, and all use guanosine nucleotide (GTP) in transesterification reactions that lead to ligation of the flanking mRNA exons. T4 introns are clear structural members of group IA2, which are prevalent in Eucarya (993). Each intron contains an ORF that is located on the periphery of the intron structure and does not interfere with the catalytic activity of the RNA. The ORF products, designated I-TevI, I-TevII, and I-TevIII, are DNA endonucleases involved in the “homing” or dissemination of the intron DNA into intronless sites of homologous sequence. Homing enzymes are also commonly encoded by group IA introns of Eucarya. The T4 I-Tev enzymes are related to the non-intron-encoded Seg and Mob endonucleases distributed throughout the T4 genome (see below) (988).

T4 introns are similar to other group I introns in that they fold into a “core” secondary structure involving the paired regions designated P3, P4, P6, and P7 (151). The catalytic RNA center has binding sites for GTP and for Mg2+, which is important for proper folding of the RNA. An internal RNA guide sequence (usually located in P1) is important for properly positioning the 5′ exon with the 3′ exon splice site. Folding of the T4 td intron into the catalytically active RNA is affected by host RNA chaperones, such as the E. coli RNA-binding proteins StpA, ribosomal protein S12, and Cyt-18 (179, 1140, 1238). Splicing in vitro can occur without these chaperones. Most of what is known about RNA catalysis by group I introns, including those of T4, derives from experiments conducted on the Tetrahymena introns (150, 152). The similarity between T4 introns and group I introns of Eucarya is thought to reflect a common ancestry (993).

Although the td intron was identified by the sequence disparity between the DNA, RNA, and protein, the nrdB and nrdD introns were detected by in vitro labeling of the excised intron with [α-32P]GTP (341). This approach has emerged as a general method of identifying group I introns in mRNAs (915), showing that they are variably distributed among different groups of phage and bacteria. Other T-even phages (including the recently sequenced RB69 genome [J. Karam et al., personal communication) lack one or more of the introns (247, 882). In phage RB3, for example, the nrdB intron and its homing endonuclease, I-TevII, are intact and functional whereas the T4 I-TevII is partially deleted and inactive (247).

More recent work on phage group I introns has focused on phage of gram-positive bacteria. Such introns are present in lysin genes of lambdoid phages infecting Streptococcus thermophilis (279), thymidylate synthase (thy) of Bacillus subtilis phage B22 (42), and the DNA polymerase genes of B. subtilis phages SPO1, SP82, 2C, and phi e (336). Three introns disrupt orf142, and two introns disrupt the large subunit of ribonucleotide reductase2 (nrdE) of Staphylococcus aureus phage Twort (614, 615); this phage, the first ever identified and described, therefore has at least five functional group I introns. As in T4, phage and bacterial group I introns are usually located in important genes for enzymes of DNA metabolism and usually are inserted in or adjacent to codons for conserved amino acids (614). The distribution and ancestry of group I introns in phage populations have been discussed (251); expression of the homing endonuclease, the cleavage specificity of these enzymes, and the likelihood of a phage infecting a cell where introns are present can all impact their distribution.

Although inteins (intervening sequences excised at the protein level) have been identified in other bacteriophages (863), none have yet been observed in T4 proteins or proteins of T4-like phages.

mRNA and tRNA Turnover

The early T4 literature on RNA processing and mRNA decay has been reviewed (962, 1166; also see reference 359). An RNA helix at the 5′ end of a transcript stabilizes the mRNA against degradation; the T4 gene 32 5′ hairpin is well documented to confer stability on its mRNA (340, 658). Host-encoded enzymes (such as RNase E), comprising an RNA “degradosome,” directly participate in the decay of T4 mRNAs (142, 795; reviewed in reference 359). However, the phage does not appear to modify the RNA degradosome or to encode any accessory proteins.

T4 does encode a riboendonuclease, RegB, that inactivates numerous early mRNAs by cleaving them at the SD sequence, GGAG (942, 943, 954). RegB also decreases the chemical half-life of early mRNAs, whereas middle and late mRNAs are neither cleaved nor destabilized. It appears that RegB recognizes a structured conformation of the GGAG sequence that is presented or stabilized by the 30S ribosomal protein S1 (628). It is not clear how RegB-mediated cleavage at these sites is affected (or not) by the covalent modification of S1 directed by the T4 ModB ADP-ribosylation enzyme. Kai and Yonesaki (494) described effects of mutations in dmd that lead to the accumulation of discretely cleaved mRNAs of middle and late mRNAs. The presence of the wild-type dmd gene, directly or indirectly, stabilizes these T4 mRNAs; RNase I (also called RNase M [1052]), among others, was implicated in the mRNA cleavage. As mentioned in the discussion of transcription termination, the goF product is also implicated in mRNA degradation.

On infection of certain E. coli strains, the 26-aa polypeptide encoded by the T4 stp gene activates the latent DNA and RNA restriction system of the host prr locus. The prrC anti-codon nuclease cleaves Lys tRNA, the most frequently used tRNA for T4 protein synthesis. While stp would serve to self-destruct the mRNA translation of the infecting phage, the T4 genes pnk and nlA encode the requisite 3′-phosphatase-polynucleotide kinase and RNA ligase, respectively, to restore the functional tRNA Lys (859). Quite possibly stp and prrC represent components of an evolutionarily important RNA restriction system, and the T-even phages, in their various hosts, employ tRNA cleavage reactions to exclude the propagation of related viruses (see below) (859).

Proteolysis

Another interesting degradative “restriction system” operating on the translational apparatus during T4 infection is the Gol-Lit interaction (1021). The defective prophage e14 present in certain E. coli strains encodes a latent metalloprotease (Lit, for “late inhibition of T4”). During the late stages of the T4 infection cycle, Lit is active in cleaving host translation elongation factor EF-Tu between amino acids Gly59 and Ile60. These residues are central to the RGITI motif of the Mg-GTP-binding domain (1231). Consequently, all translation is inhibited, albeit at a time shortly before lysis of the T4-infected cells. Activation or binding of the Lit protease is promoted by T4 Gol (for “grows on Lit-producing bacteria”), a 29-residue peptide (AVMGMVRRAIPNLIAFDICGVQPMNSPTG) corresponding to residues 93 to 122 of the gp23 protein (78). Lit associates with the EF-Tu-GDP open complex, which appears to be stabilized by the Gol peptide, resulting in EF-Tu cleavage. Because the Gol peptide is a segment of the N-terminal proximal region of the phage gp23 head protein, it has been proposed that binding of EF-Tu to the Gol domain may also assist in the assembly of phage capsids during synthesis of gp23 (78). The Gol (gp23)-EF-Tu interaction is just one of several associations between viral proteins and cellular translation factors that suggest ubiquitous strategies for viral development and maturation (78).

The T4 Pin protein (1012) inhibits the host Lon protease. As one consequence, truncated peptides of T4 nonsense mutants are more stable than those of E. coli.

DNA METABOLISM, REPLICATION, RECOMBINATION, AND REPAIR

A large fraction of the T4-encoded enzymes with known metabolic functions are devoted to DNA metabolism. T4 not only encodes all of the components of its own replisome and recombination systems but also makes most of the enzymes involved in preparing nucleotides for incorporation into DNA. A number of these duplicate host enzymes (aerobic and anaerobic ribonucleotide reductases, thymidylate synthase, and thymidine kinase). Others are uniquely related to the utilization of hydroxymethylcytosine rather than cytosine in T4 DNA (dCTPase, dCMP hydroxymethylase, dHMP/dTMP/dCMP kinase, and DNA glucosyl transferases that sugar coat the HMC-containing DNA to protect it from attack by certain host nucleases).

Many known T4 proteins function only as parts of macromolecular complexes (14). This is true not only for the assembly of the complex phage particle (see below) but also for most of the T4 enzymes of nucleotide biosynthesis, DNA replication, recombination, and transcription. Understanding these complex protein machines requires not only work with purified proteins but also analysis of the effects of mutations in these proteins in vivo and examination of the conformational changes that occur in the proteins while they interact with different components of the complexes.

Enzymes of Nucleotide Metabolism

Among the best understood of these machines is the T4 nucleotide precursor complex (reviewed in references 348 and 695). It takes both cellular nucleoside diphosphates (NDPs) and the deoxynucleoside monophosphates (dNMPs) from host-DNA breakdown and converts them into deoxynucleoside triphosphates (dNTPs), in the proper ratios for T4 DNA (two-thirds A+T, in contrast to the 50% A+T found in the host). The precursor synthesis occurs at the appropriate rate for normal T4 DNA replication even when DNA synthesis is otherwise blocked, implying that the regulation is not via feedback inhibition. Proteins of the nucleotide-precursor complex, which includes two host proteins, are thought to interact with the replisome as they funnel nucleotides directly into the DNA replication complex. T4 ssb (gp32) is thought to be an essential coupler of the precursor and replication complex (1161). The interactions at all these levels have been documented by such methods as in vivo substrate channeling, intergenic complementation, cross-linking, immunoprecipitation, and affinity chromatography, as well as by kinetic studies of substrates moving through the purified precursor complex (1161). One consequence of the tight coupling is that dNTPs entering permeabilized cells must be partly dephosphorylated to enter the complex and must then be rephosphorylated to enter the DNA, so that exogenous dNTPs are used severalfold less efficiently than are dNMPs or dNDPs. A similar complex has also been documented during anaerobic growth (696, 900), but the exact relationship of the T4 two-subunit anaerobic NTP reductase to the other enzymes of the complex is not yet clear. Since the T4 dCDPase/dUDPase is also a dCTPase/dUTPase, the pathways for dTMP/dTTP and HMdCMP/HMdCTP synthesis would not be disrupted by reducing the nucleotides at the triphosphate rather than the diphosphate level. The process of host DNA breakdown clearly also channels nucleotides into this complex in a way that is not subject to competition by exogenous thymidine (605), but the nucleases involved have not been identified as members of the nucleotide precursor complex.

DNA Replication Proteins

From a combination of genetic experimentation and virtuoso biochemical and biophysical characterizations has emerged a detailed understanding of the functions and interactions within the T4 replisome (53, 826, 830). The seven T4 proteins encoded by genes 43 (DNA polymerase), 44 and 62 (sliding clamp loader), 45 (sliding clamp), 41 (DNA helicase), 61 (primase for lagging-strand synthesis) and 32 (ssDNA binding protein) make up the basic replisome, a biological machine (14, 15) that can move the replication fork through model templates at in vivo speeds (Fig. (Fig.7).7). Additionally, RNase H (rnh) and DNA ligase (30 = lig) are required to seal Okazaki fragments and other interruptions in DNA, and T4 gp59 accelerates the loading of the gp41 helicase in vitro (38, 478). The DNA arrest phenotype of gene 59 mutants had suggested that gp59 is not required during origin initiation but is required for recombination-dependent DNA replication (see below). The 5′-to-3′ exonuclease function of host DNA polymerase I can substitute for defective T4 RNase H (427) and E. coli ligase can substitute for T4 ligase, if the T4 rII genes are mutated (59, 159, 504, 580, 776). Amino acid alignments and three-dimensional structures of several of these proteins (or segments of them) (799, 800, 982-983) show homologies to replication proteins of many other prokaryotic and eukaryotic organisms. The two most striking examples are the DNA polymerase, gp43, and the sliding clamp of T4, gp45. Like the eukaryotic sliding clamp, T4 gp45 forms a pseudo-hexameric protein which is trimer of a protein with two similarly folded domains. In contrast, the E. coli sliding clamp is a dimer of trimers. Moreover, the clamp loader of T4 can partially substitute for a eukaryotic clamp loader in an in vitro replication system (1135).

FIG. 7.
The T4 replisome. A model of a T4 DNA replication fork and the central proteins is shown. Numbers indicate the gene encoding each protein. See the text for a description of the functions of each protein. Reprinted from reference 478 with permission from ...

Mutations in many other genes affect DNA replication in vivo (Table (Table2),2), because these genes are important for recombination-dependent DNA replication and repair of broken forks (see below). Since DNA is constantly assaulted by intrinsic and extrinsic damaging agents, DNA replication and recombination are tightly correlated and should not be considered in isolation. Studies of T4 have paved the way to understanding these relationships (200, 572, 575, 577, 668, 771).

DNA replication genes are scattered throughout the genome, with a major cluster that includes the DNA polymerase (gene 43); most of these genes are transcribed from both early and middle promoters. Coordination of the T4 DNA replication functions is achieved by the assembly and disassembly of protein complexes that appear to use stretches of DNA covered with ssDNA-binding protein, gp32, as scaffolds (283, 765, 766, 774, 793, 1161). In wild-type T4, the syntheses of the leading and lagging strands are coupled, but both in vitro and in vivo leading-strand synthesis can be uncoupled to proceed on single-stranded templates, or by displacement of one parental DNA strand on double-stranded templates (488, 788).

In contrast to the E. coli replisome, the T4 replisome has not been isolated as a functional complex. Possibly, the weak interactions of the core replisome components facilitate interactions of DNA polymerase with different accessory replication and recombination proteins, as discussed below. These various interactions can be correlated with the three-dimensional structures of the DNA polymerase, the sliding clamp and the core of the ssb, gp32, from T4 and the related phage RB69 (983, 1141, 1146). Extensive analysis of mutator and antimutator strains has also facilitated our understanding of these interactions (827, 904, 906, 909).

Replication and initiation of late transcription are strongly coupled by the requirement for the sliding clamp of DNA polymerase, gp45, to transform closed to open RNA polymerase-promoter complexes, and the requirement for ssDNA interuptions to load the clamp (552a, 951, 1082, 1173). The replication complex moves along the DNA at 10 times the speed of the transcription complex. Because both processes proceed in both directions, frequent collisions must occur. In vitro evidence shows that T4 transcription and replication complexes can pass each other when they meet head-on, with the RNA polymerase changing templates without interfering with the total processivity of transcription (650). It now appears that this surprising and very useful ability is not universal. For E. coli (294), evidence indicates that head-on collisions between DNA and RNA polymerases retard the movement of both.

Initiation of DNA Replication

The first round of T4 DNA replication is initiated from one of several different origins (Table (Table1;1; Fig. Fig.3).3). Replication is mediated by T4-encoded enzymes, with the exception that the host RNA polymerase synthesizes the primers for leading-strand initiation at origins (577, 668) and that host DNA polymerase I can remove RNA primers of Okazaki fragments (427). T4 primase then synthesizes primers for Okazaki fragments. In its absence, unidirectional displacement synthesis occurs (46, 47, 778, 779, 788). The displaced strand is later copied by a recombination-dependent “join-cut-copy” mechanism (discussed below). Combinations of density shift with electron microscopy analyses (199, 200) have shown that in most cases only one origin is used and is used only once, probably because at the time of origin initiation there are limited supplies of DNA polymerase and other replisome components. When the timing of early-gene expression is distorted by mutation, origins can be used repeatedly (for a review, see reference 563). As soon as the first replication forks have reached an end, recombination intermediates compete effectively for assembly of replisomes, and because T4 chromosome ends are circularly permuted, less dependence on specific origins is observed (200).

Four major DNA replication origins have been mapped to specific sequences, which are different in each case. The transition from RNA primers to leading-strand DNA synthesis in vivo occurs at several sites located over 1 kb downstream of the promoter that initiates primer transcripts (778, 779, 1109). At oriA, oriF, and oriG, the priming transcripts are initiated from MotA-dependent middle promoters (577). Priming of DNA synthesis by a transcript requires that the transcript reinvade the DNA, forming an R-loop. This reinvasion can be facilitated by global torsional stress in the DNA. Indeed, in vitro initiation from oriF has been achieved with an RNA primer that had been taken up by a supercoiled plasmid (830). The end of the R-loop used in these experiments was designed to be the same as in R-loops isolated from replicated DNA in vivo and probed for single strandedness of the displaced DNA strand. By analogy to E. coli (551a), this RNA end was postulated to be processed from a longer transcript by RNase H (133). However, this site is different from the major in vivo priming sites detected by primer extensions on nascent DNA (779). These occur in the terminator region between genes uvsY.-2 and uvsW and require little or no processing. Possibly, both priming mechanisms are used in the oriF region.

In contrast, oriE can still function when torsional stress is reduced (for instance, by mutation in the host gyrase [789]). At oriE, the priming transcript is initiated from an early promoter. oriE function depends, in addition, on a small protein, RepEB, and the auxiliary protein RepEA, both encoded by transcripts related to the primer. In contrast to the other origins, oriE contains repeat sequences, the so-called iterons (779, 1109). The binding of RepEB to one or more of these iterons is required for oriE to function (Harvey et al., unpublished). It is postulated that binding of RepEB to the iterons facilitates the loading of a DNA helicase and that unwinding by the helicase can compensate for the lack of global torsional stress in oriE.

The different structures and functional requirements of different T4 origins may be considered as models for poorly understood complexities of other multiorigin chromosomes. For example, in the major origin of E. coli, oriC, leading-strand synthesis can be primed by primase-dependent or RNA polymerase-dependent RNAs (558); E. coli can use other origins, oriK, which, like T4 origins, depend entirely on transcripts for priming (34). Similarly, different yeast origins are detected in different labs using different methods (1042).

Recombination and Recombination-Dependent DNA Replication

The discovery of recombination provided a powerful argument that phages can be used as model systems (411), and a strong connection between replication and recombination was suspected early on (1129). Our current view of these tight interconnections and the interactions with the transcriptional and posttranscriptional developmental program of T4 are summarized in Fig. Fig.44.

Although the onset of DNA replication is largely dependent on replication origins, most T4 replication forks are initiated by using intermediates of recombination as DNA primers at more or less random positions throughout the genome. Because origin-dependent DNA replication is inactivated during the developmental program, recombination-deficient T4 mutants arrest DNA replication prematurely.

There are several different recombination-dependent replication modes, which require different recombination proteins; these have been thoroughly reviewed (768, 769, 784). In undamaged chromosomes, early T4 join-copy recombination depends on origin-dependent replication; it is initiated from the ssDNA at the unreplicated end of the template for lagging-strand synthesis. In damaged T4 chromosomes, similar mechanisms can be used to repair broken replication forks (575) (see below). When origin-initiated DNA replication is inhibited, recombination can occur, but it begins later and requires additional nuclease activities (111). Electron micrographs of such T4 DNA intermediates provided the first compelling evidence for annealing of single strands as one way to initiate recombination (pathway I in Fig. Fig.4)4) and for the importance of branch migration in homologous recombination (111). Under replication-deficient conditions, no viable progeny particles are produced. There is no late join-cut-copy recombination, no packageable DNA concatemers are formed, there is little late transcription (since that is dependent on DNA replication), and no heads are formed that can be filled.

The main genes required for join-copy recombination-replication (Fig. (Fig.4)4) (in addition to the SSB gene 32 that is required for most aspects of DNA repication, recombination and repair) are uvsX, uvsY, 46, and 47 (Table (Table2).2). The 46 and 47 proteins, acting in a complex, have similarity to the E. coli SbcBC and RecBC proteins and the eukaryotic Rad50/Mre11 complex. The strand invasion UvsX protein is a structural and functional homologue of the E. coli RecA protein and the eukaryotic Rad51, Dmc1, and Rad54 proteins (69, 192, 739). As expected, if this is the major pathway to initiate T4 replication forks, defective mutants arrest DNA replication after limited origin replication has occurred. The corresponding genes are expressed from early and middle promoters, concomitantly with the replication proteins acting at the fork. Thus, this pathway can operate early.

In contrast, the endoVII (49) and terminase (17) genes required for join-cut-copy recombination-replication are predominantly expressed late and therefore are exclusively part of a late recombination pathway that has been called the “join-cut-copy” pathway (768, 769). The late uvsW gene, encoding an RNA-DNA helicase and a functional homologue of the E. coli RecG protein (132), is probably also specifically important in this late recombination pathway (722). This pathway is also implicated in horizontal transfer between different phages of DNA segments with limited homology (777, 784).

Together, these mechanisms generate the branched, concatemeric intracellular T4 DNA. This DNA is debranched in vivo by T4 endonuclease VII (gp49), which can cut Holliday junctions, Y-junctions, and mismatched base pairs in heteroduplex DNA (reviewed in reference 522), and by the largest (70-kDa) subunit of the heteromeric terminase (288). As mentioned above, genes 49 and 17 both code for several nested proteins by initiation from internal ribosome binding sites, and the function of EndoVII (gp49) in vivo depends on the regulated timed synthesis of the two nested proteins (reviewed in reference 784). This can now be correlated with the three-dimensional structure of EndoVII (883).

DNA Repair

As in other organisms, damage and mismatches in T4 DNA can be repaired in several different ways, and repair defects result in increased sensitivities to such damage or increased mutation rates. The consequences of such mutations have been summarized by Bernstein and Wallace (67).

The first mechanism shown to repair UV-damaged T-even DNA was photoreactivation (245). It is now known that the host enzyme responsible for this repair causes the reversion exclusively of pyrimidine dimers to the monomeric state (reviewed in references 233 and 234).

Harm (384) first isolated DNA repair mutants with mutations in T4 genes that are now called denV and uvsX. EndoV, the product of denV, is the prototype of a base excision repair protein. It has both N-glycosylase and abasic lyase activities (222, 656), which incise the DNA (forming a covalently linked protein-DNA intermediate). Together, these activities remove the pyrimidine dimers to allow resynthesis by DNA polymerases, notably including E. coli PolI (1056) and the T4 ssDNA-binding protein, gp32 (764). The profound difference in UV sensitivities of T4 and T2 is due to the presence of denV in T4 but not in T2 (222, 384).

The T4 uvsX gene encodes a RecA homologue, the major protein required for invasion of ssDNA into homologous double-stranded DNA (dsDNA) to form D-loops, which can be extended to form two heteroduplexes joined by Holliday junctions. The radiation sensitivity of uvsX mutants is now understood to be a consequence of defective recombination-dependent DNA replication that can repair or bypass DNA lesions. Therefore, all recombination-deficient mutants (Table (Table2)2) are also defective in DNA repair (60, 68, 1056; reviewed in references 67, 572, and 575).

Heteroduplex (or mismatch) repair of T4 DNA in vivo and in vitro is mediated by EndoVII, the enzyme that cuts Holliday junctions (522, 526, 793), not by MutHLS-like enzymes. The specificity of this activity is thought to contribute to the exclusion of viable recombinants between different T-even phages whose sequences have diverged (305, 784).

MOBILE ENDONUCLEASES, GENE TRANSFER, AND GENE EXCLUSION

Following discovery of group I introns in T4 (see above) (991), site-specific endonucleolytic DNA cleavage by the protein of the intron ORF was demonstrated (882); reviewed in reference (178). The three intron ORFs of T-even-like phages are I-TevI (td intron), I-TevII (nrdD intron), and I-TevIII (nrdB intron). In T4, I-TevIII is partially deleted so that the endonuclease activity is absent; the T4-related phage RB3 has an intact ORF, and endonucleolytic activity of the I-TevIII enzyme is detected (247). Each endonuclease recognizes a so-called “homing” site that is cleaved by the enzyme, with the double-strand break (DSB) serving as a recombination site for insertion, or conversion, of the intron. Thus, intronless sites, when present in mixed infections with intron-containing phage or other DNAs containing the intron and its ORF, are efficiently converted to contain the intron. The apparent DSB recombination process involves the I-Tev nuclease only for the generation of the DSB. The specificity of these nucleases involves a site on the DNA for binding and a separate cleavage site, which for I-TevI is 23 to 25 bp upstream of the insertion site (202). Subdomains for DNA binding by the I-TevI nucleases include a zinc finger, an α-helix, and a helix-turn-helix. Homing endonucleases of introns can be viewed as systems that target localized gene conversion events, mobilize specific DNAs from one chromosome to another, or, as for SegF (see below), effectively exclude genes or larger regions from “invading” a related chromosome.

At least 15 T4 genes (including the I-Tev genes) belong to two of the four structural families of homing endonucleases (163, 992) defined by the conserved sequences GIY-YIG, LAGLIDADG, H-N-H, and His-Cys (49). Sharma et al. (988) recognized and described the segA-segE set of T4 proteins, which are not associated with an intron, and provided convincing evidence for the endonuclease activity of SegA. Kadyrov et al. (489, 490) later demonstrated that segE promotes its own transfer to the related phage RB30, which does not carry this gene. They reported that efficient transfer requires bases upstream and downstream of the segE cleavage site, and they cited unpublished data that SegB and SegD can initiate similar nonreciprocal genetic exchange. The location of SegB in the tRNA gene cluster suggests that its cleavage site is in or near these genes and that it could be responsible for maintaining (recombinational exclusion) or transferring the tRNAs. Errors near the putative start codons in the initially published sequences of the three seg genes (which were sequenced from clones) have been corrected (489, 490). This is consistent with the suggestion that they are expressed and lethal to the host and that mutated versions were selected during cloning. Indeed, the recombination-dependent gene exclusion in the T4 56-69 region (305) is due to a DSB generated by the product of the gene 69 ORF, prompting the renaming of the gene as segF (51). A similar localized gene conversion activity in the gene 32 (encoding the essential T4 SSB protein) region has been recently demonstrated for the product of ORF 32.1, which has been renamed segG (48; Q. Liu, A. Belle, D. A. Shub, M. Belfort, and D. R. Edgell, submitted for publication).

I-TevI, I-TevII, and SegA through SegG all appear to have the GIY-YIG family signature (cited in references 51 and 202; also see the pfam alignment at http://www.sanger.ac.uk/cgi-bin/Pfam/getacc?PF01541). SegF aligns in the N-terminal half with the GIY-YIG domain, but in the C-terminal half it aligns with MobD, a member of the H-N-H family (51, 305).

I-TevIII and T4 Mob proteins (MobA through MobE) group with the H-N-H family of DNA endonucleases, which are rooted by the sequence and structure of the DNase colicin e7 (microcin e7). The H-N-H signature sequence also includes the mobility endonucleases of group II introns and the E. coli restriction endonuclease McrA (337, 992). Reiterative PSI-BLAST analyses of the uncharacterized T4 ORFs may yet yield more members of these DNA endonuclease, which appear to be surprisingly abundant in the T4 genome.

It is not yet clear how many of the mob genes are actually expressed during T4 infection. Two of them—mobA, between genes 39 and 60, and the nuclease gene in the T4 nrdB intron—seem clearly to be pseudogenes and are nonfunctional (247). segD is situated in reverse orientation with respect to adjacent genes, with antisense RNA from gene 24 occurring between segD and the nearest promoter from which it could be expressed. No functional or homing studies have yet been carried out for any of the mob genes, although mobD has been successfully cloned and overexpressed (Kutter, unpublished). The role that these enzymes play in gene mobility and transfer and/or in gene exclusion and recombination processes merits further analysis.

T4 PARTICLE, INFECTION, AND LYSIS

T-even phages build some of the most complex virus particles known (Fig. (Fig.11 and and8).8). They devote more than 40% of their genetic information to the synthesis and assembly of the prolate icosahedral heads, tails with contractile sheaths, and six tail fibers that contribute to their very high efficiency of infection. Most of the genes for the structural proteins are transcribed in the clockwise direction on the standard genomic map. The genes responsible for each substructure are largely clustered, with these clusters distributed over more than half of the genome (Table (Table1;1; Fig. Fig.3).3). There are some interesting exceptions to the clustering. For example, the tail is built on a baseplate made of a hub and six wedge components, and each of the substructures is encoded by a gene cluster. However, gene 5, one of the five genes involved in assembling the hub, is actually located with the genes for the wedge, while a wedge gene, gene 25, is located with hub genes; these two clusters are separated by the head and other tail proteins. Interestingly, each cluster also contains a replication origin and the direction of transcription switches within each cluster.

FIG. 8.
Structural components of the T4 particle. Features of the particle have been resolved to about 3 nm. The positions of several head, tail, baseplate, and tail fiber proteins are indicated (see the text for details and references). Adapted and reprinted ...

Exquisite genetic and biochemical analyses revealed the complex assembly pathways of the T4 particle (89, 186, 272). Twenty-four proteins are involved in head morphogenesis, and there are 22 for tail morphogenesis and 7 for tail fibers, including one for tail fiber attachment (Tables (Tables22 and and3).3). As described below, 5 of the 54 proteins are catalysts for assembly rather than components of the final virion. In the assembly pathway, the head, tail and tail fibers are assembled independently. A head and tail are associated, and then the six tail fibers attach to the baseplate (250).

Heads

Of the 24 proteins assigned to head morphogenesis, 16 are involved in prohead formation and maturation, 5 are responsible for DNA packaging, and 3 complete and stabilize the head. Only 10 of the 16 genes for prohead formation are essential; these include GroEL, the one host-encoded protein involved in head assembly. This contrasts with phage lambda, where GroES, DnaK, DnaJ, GrpE, and GroEL are all essential (187, 317, 318, 1078). van der Vies et al. (1115) showed that T4 gp31 can substitute for the function of GroES. Since then, crystallographic analysis revealed that gp31 forms a heptameric ring that is quite similar to the GroES structure. However, T4 gp31 has an extra loop that makes the inner cavity of the GroEL-gp31 complex larger so that it can accommodate the folding intermediate of gp23, the major capsid protein (455). The head is assembled on the initiator complex, which is a 12-mer of gp20 arranged in a ring. The scaffold, made of gp22-gp21 (stoichiometry = 576:72) and the capsid protein, gp23, are assembled onto the initiator, which eventually becomes the portal vertex. Pentamers of gp24, which is 28% identical in amino acids residues to gp23, are placed at the other 11 vertices. After the scaffold is completely surrounded by gp23 and gp24, the T4 prohead protease, gp21, degrades the scaffold and cleaves most of the other head proteins, including gp23 and gp24. This creates space in the cavity of the prohead. The prohead thus formed is then detached from the membrane (ESP = empty small particle). Jardine and Coombs (471, 472) demonstrated by pulse-chase experiment that ESP then initiates DNA packaging and forms the ISP (initiated small particle), which contains about 10 kb of DNA. The ISP is expanded about 15%, resulting in a twofold (1.153 = 1.98) increase of the inner volume (ILP = initiated large particle). The resulting mature head is much more resistant to any kind of perturbation.

DNA Packaging

Packaging of DNA is initiated from double-stranded ends. For intracellular concatemers, the terminase complex initiates packaging by first generating ends. This complex contains a small subunit, gp16, and large subunits, gp17, gp17′ and gp17" (286, 288). The nuclease activity of terminase resides in the products of gene 17 (74, 75, 288). The terminase-DNA complex is translocated from the cytosol to the portal protein gp20 at the vertex of the head to form the “packasome” (893), which uses the energy of ATP hydrolysis to translocate DNA into the head. Expansion of the head is coupled to entry of DNA (471, 472). There is a symmetry mismatch between the neck initiator complex, which has 12-fold symmetry, and the head, which has 5-fold symmetry. It has been suggested (399) that the neck rotates during DNA packaging. The packaging mechanism cuts the DNA when the head is filled, and it appears that EndoVII trims branches of DNA even after packaging has been initiated (523). The head full of DNA is about 3% longer than the genome size, accounting for the circular permutation of T4 genomes, with terminal redundancy of each genome; this circular permutation is the basis for the circular T4 genetic map (1048, 1049, 1073). Shorter or longer phage heads are occasionally formed, due to assembly errors that are increased by specific mutations in some head genes (256) or by incorporation of arginine analogues (194). The amount of DNA packaged into the head is altered accordingly. While short-headed phages cannot infect singly, they can complement each other to give a normal infection (767, 770, 782). After packaging, gp13, gp14, and six trimers of gp wac (whisker or fibritin) bind to the portal vertex to complete the head, which then binds to the tail.

Although the complex head assembly pathway has resisted full in vitro reconstitution, either T4 or foreign DNA can be packaged in vitro into empty heads. These can then be assembled in vitro with tails and tail fibers to form infectious or transducing particles (434, 802, 893).

Nearly all the genes for virion structural proteins, the assembly catalysts, and the scaffold appear to be present in the genomes of T4-like phages examined to date (701, 1069), although some exceptions have been noted for the Vibrio phage KVP40 (E. S. Miller, J. F. Heidelberg, J. A. Eisen, W. C. Nelson, A. S. Durkin, A. Ciecko, T. V. Feldblyum, J. Lee, B. Szczypinski, O. White, I. T. Paulsen, W. C. Nierman, and C. M. Fraser, submitted for publication). Two T4 head proteins—encoded by soc and hoc—are nonessential. The unusual locations of their genes, their absence in some T4-related phages, and the fact that they are added only after head expansion during assembly are consistent with their being a later acquisition. They are possibly retained because they enhance particle stabilization. The dispensable nature of Soc and Hoc has provided a rationale for a T4 phage display system capable of presenting large polypeptides on the capsid surface (916, 918).

Baseplate and Tails

The tail and tail fibers are responsible for the high efficiency of T4 infection. The tail is made of a baseplate and two slender cocylinders. The inner cylinder, called the tail tube or simply tube, consists of 144 subunits of gp19 arranged in 24 stacked hexameric rings. The inner space of the tail tube allows for the passage of phage DNA. The same number of gp18 molecules form the outer tail sheath, with the subunits arranged in the same manner as gp19. Each stacked sheath ring is offset 17 degrees to the right of the one below it, which gives an apparent right-handed helix (753). While the noncontracted tail sheath is 98.4 nm long, the contracted tail sheath is only 36 nm long and the offset (or twist angle) of sheath proteins is increased to 32°. The assembly and three-dimensional reconstruction of the tail and tail sheath have been reviewed (186).

The baseplate consists of a hub surrounded by six wedges, which are assembled independently. Hub assembly is fairly complex. The six products of genes 5, 27, 29, 26, 28, and 51 have been reported to be involved in the assembly. gp51 is a catalytic protein, while gp26 and gp28 have not been rigorously proven to be components of the hub or baseplate. gp5 and gp27 associate first. The hub is completed by binding of gp29 to the gp5-gp27 complex. It appears that some structural modification of gp29 is necessary before associating with the gp5-gp27 complex. Wedge assembly is initiated by association of gp10 and gp11, followed by addition of gp7, gp8, gp6, gp53 and gp25, in that order (except that gp11 can be added later, along with gp12). In the absence of any of the other components, the assembly stops at that point and the remaining components are left free in “assembly-naive states” (532). After six wedge segments bind to the hub, gp9, gp12, gp48, and gp54 are added.

The reported stoichiometry of the subunits has been summarized (186), but some corrections have since been made. There are 18 molecules of gp9 instead of 24 (560), 18 each of gp10 and gp11 instead of 12 (1239), 3 each of gp5 and gp27 instead of 6 (498), and 12 of gp8 (P. G. Leiman, unpublished data). The stoichiometry of gp3 was not known but has now been determined to be 6 (L. Zhao, unpublished data). Three-dimensional structures of gp11 (633), gp9 (560), and the gp5-gp27 complex (498) have been determined by X-ray crystallography. Interestingly, all these structures (except gp8) involve trimers of each component.

Baseplate morphogenesis appears to occur in association with the cell membrane. The baseplates remain attached to the membrane by 300-Å fibers from the six corners of the baseplate during the remainder of phage assembly until the time of cell lysis, as shown by electron microscopy (1003). This is seen even in mutants lacking gp12, which encodes the short tail fiber involved in irreversible phage binding during infection (see below). The finding that gp7 has a predicted membrane-spanning domain near its C-terminus (see below) suggests a possible mechanism for this attachment.

The presumed localization of the tail lysozyme gp5-gp27 complex in the baseplate is shown in Fig. Fig.9.9. The baseplate protein gp5 is a natural chimera. A lysozyme domain, a paralog of the soluble lysozyme of T4 (787), is inserted into the center of a structural baseplate component. The overall shape of the trimeric gp5 resembles a torch, where the N-terminal domains, together with the trimeric gp27, form a cup, the lysozyme domains form the rim, and the C termini of gp5 form the handle. This “handle” is the most conspicuous structure—a three-stranded beta-helix 110 Å long and 28 Å wide. The primary structure of the β-helix region has a peculiar motif of VXGXXXXX (8 residues) repeated 12 times. The cross-section of the cylinder is not a circle but, rather, a triangle, with the glycine at position 3 located at the edges to form a kink. Among some T4-related phages (e.g., RB69, RB49, KVP40, and S-PM2) the beta-helix is well preserved, but there is some indication that its length can vary (F. Arisaka, unpublished data).

FIG. 9.
Three-dimensional image reconstruction of the T4 tube-baseplate from cryoelectron microscopy. (A) Stereo image view of the baseplate and part of the tube at 17 Å resolution. The top quarter of the baseplate has been removed to show the internal ...

The gp5-gp27 heterohexameric complex is attached at the tip of the tube. When the tail sheath contracts and the tail tube protrudes from the bottom of the baseplate, the triple-stranded β-helix is considered to play a role like that of a needle to puncture the cell. gp5 is the only protein in the tail that experiences processing; the peptide bond between Ser351 and Ala352 is cleaved during assembly, but the C-terminal domain stays associated with the other part of the molecule in the mature virion. The lysozyme activity is activated only when the C-terminal domain is detached from the other part of gp5. It has been proposed (498) that the C-terminal domain of gp5 is detached from the lysozyme when the needle penetrates into the outer membrane upon infection (see “Infection and superinfection exclusion” below). The activated gp5 lysozyme in vitro is monomeric (497).

The complete assembly of the tail requires two chaperones, namely, gp51 and gp57A (1015). In the established model (531), gp51 is involved in the hub assembly while gp57A is involved in assembly of both the short and long tail fibers. gp57A consists of 79 aa, and more than 90% is α-helix (391, 699). Although the molecular nature of the protein has been worked out, the interactions with the short and long tail fibers are unknown.

The short tail fiber is a trimer of gp12; its partial three-dimensional structure has been reported (1118). It consists of three domains called the pin (N terminus), shaft, and head (C terminus). The shaft is mainly β-helix and β-spiral. gp11 is located at the tip of the tail pin and bound to the middle part of the P12 trimer, at a site where the P12 shaft is bent about 94°.

gp9 forms the socket of a long tail fiber (1105) consisting of four gene products, gp34, gp35, gp36, and gp37, where gp34 and gp37 are the proximal and distal long tail fibers, respectively. gp35 and gp36 attach to the distal fiber, forming the junction between the half-fibers. Presumably one or both interact(s) with the tip of the whiskers (fibritin; wac). Structural analysis of the C-terminal portion of the whisker (1051) revealed a three-stranded coiled-coil structure with a beta structure “propeller” at the C terminus. This beta structure is thought to bind the bend or “knee” in long tail fibers to facilitate tail attachment to the baseplate. The assembly of the tail fibers requires two molecular chaperone-like proteins, gp57A and gp38. In a major difference from the T4 system, T2 gp38 (which is unrelated to T4 gp38) is a structural component of the tail fibers; it, rather than the C terminus of gp37, recognizes the host bacterium (750, 751).

Infection and Superinfection Exclusion

The initial energy for infection is provided by the baseplate, which is built like an exquisite, “cocked” mechanical device. gp9 is the stabilizer between the long tail fibers and the baseplate. After at least three of the six long tail fibers bind to a glucose residue of the outer core of the lipopolysaccharide on the bacterial surface, a structural rearrangement of the baseplate from “hexagon” to “star” is triggered (190). This deploys the six short tail pins, after which the short tail fibers (gp12) previously in the baseplate firmly bind to the bacterial outer membrane at the heptose residue of the lipopolysaccharide inner core (751, 933). This is referred to as the second receptor of the phage. The conformational change of the baseplate simultaneously triggers contraction of the tail sheath, pushing the inner tube through the outer membrane. Contraction of the tail sheath appears to advance as a wave of compression transmitted through the helix-like arrangement of tail sheath annuli. The tail lysozyme (gp5), after detachment of the C-terminal “needle,” helps to digest the peptidoglycan layer and reach the inner membrane. The beautiful baseplate/needle structure (498) is reprinted in Fig. Fig.9.9. Phosphatidylglycerol in the inner membrane appears to play a role in release of the DNA through the tip of the tail tube, but the electrochemical potential across the inner membrane is necessary for the DNA to be pulled into the cytoplasm (reviewed in reference 327). In the absence of the electrochemical potential, DNA remains in the periplasm and is eventually degraded.

Host range is determined primarily by distal sites on the long tail fibers. A C-terminal region of gp37 is hypervariable in different T-even phages (390, 750), allowing for adaptation to different host receptors. The system has been referred to as a primitive prokaryotic immunity system. As shown by Wais and Goldberg (1137), T4 can grow well in a number of other gram-negative bacteria if it can gain entry, such as when the bacteria are converted to spheroplasts and the phage are treated with urea. The urea leads to contraction of the tail sheath and formation of activated phage particles that, on contact with bacterial inner membranes, can release their DNA into a spheroplast.

The initial infection leads to poorly understood membrane alterations involving the product of the T4 imm (immunity) gene. One consequence of these changes is that by about 4 min after infection, the DNA from T4 or related phages attempting to penetrate the cell envelope is released into the periplasm, where it is degraded by nucleases, resulting in a phenomenon called superinfection exclusion (665, 666). Other genes that appear to be involved in this process include sp, rIIA, rIIB, and rI, but their precise functions are not well understood.

Lysis and Lysis Inhibition

Normally, 100 to 150 phage particles have accumulated in the cell by the time lysis occurs. As in many other tailed phages, two proteins are involved in the lysis process: gpe and gpt. gpe is the so-called T4 lysozyme (1050), whose structure has been extensively studied by Mathews and colleagues (1193, 1206). Under special conditions, the gp5 lysozyme discussed above can substitute for gpe (500). gpt is the T4 holin, which, by analogy to other well-studied phagelysis systems, creates a hole in the inner membrane so that lysozyme can reach the peptidoglycan layer from the cytosol; the timing of holin assembly thus determines the timing of lysis (360, 887). In the absence of either lysozyme or the holin, lysis does not occur.

The T-even phages display a unique phenomenon, lysis inhibition, which allows them to sense when there are numerous phage around and respond appropriately to delay lysis, maximize the use of their current host, and potentially await the accumulation of additional bacterial hosts (41a, 851). Lysis is extensively delayed if more phage attack the infected cell at any time after 5 min into infection. This signal is somehow mediated by the rI protein, which regulates assembly of the t holin (851). Recently, Ramanculov and Young substituted the T4 t gene for the holin of bacteriophage lambda and showed that these lambda phage could now produce lysis inhibition if they infected E. coli that carried a cloned T4 rI gene (886, 887). T4 gprIII further extended lysis inhibition, but no other or additional T4 proteins were required. We still do not know the specific signal that gprI senses to establish lysis inhibition; possibilities include the phage DNA or the internal proteins that have been injected into the periplasm rather than the cytoplasm under these circumstances.

The classic rII genes were involved in defining the phenomenon of lysis inhibition when T4 was propagated on E. coli B strains (224). The T4 rII mutants provided an example of phage exclusion by genes of resident prophages. They are completely excluded by the lambda rexA and rexB genes expressed in lysogens. This phenomenon was elegantly used in Benzer's fine-structure analysis of the gene (56). Exclusion occurs at the time of transition from join-copy to join-cut-copy recombination and involves several enzymes important in the latter process (769, 793). The molecular mechanism of this exclusion is still poorly characterized. It has been proposed that RexB forms an ion channel that is opened after infection with T4 rII mutants or various other phages, leading to loss of ions and cellular energy (855). However, the way in which the rII proteins bypass this process is still unclear (reviewed in reference 1021). More recently (851), it was demonstrated that gprIIA and gprIIB are also primarily responsible for protecting T4-infected E. coli B cells against the attack of a P2-related resident prophage, with less severe consequences than when T4 rII mutants infect K-12 strains lysogenic for lambda. A similar phenomenon appears to be responsible for the large size of rII plaques on the lysogenic E. coli B strains (851). In that case, DNA replication is not affected and lysis does not occur until about 25 min after infection, so that a reasonable burst is produced. If the host B cell has been cured of the P2-related prophage, rII mutants show normal lysis inhibition. As first shown by Rutberg and Rutberg (947), many E. coli B strains carry a defective prophage related to P2. The primary role of the rII genes seems to be related to cellular energetics. The apparent “lysis inhibition” phenomenon seen on lysogenic B strains, rather than the phage death seen on K-12 lambda lysogens, appears to be due to the breakdown of cell energetics occuring near the normal lysis time on B cells, rather than at 12 min after infection of K-12 (lambda) cells.

RESTRICTION-MODIFICATION SYSTEMS AND PHAGE EXCLUSION

As mentioned above, the T4 nucleotide metabolism enzymes result in HMC-containing DNA that is protected from T4-encoded nucleases that degrade host DNA. These enzymes (encoded by denA, denB, dexA, and others genes) can be viewed as DNA restriction systems and also as mechanisms for generating nucleotide precursors for T4 DNA replication (139). Indeed, the DenA (EndoII) recognition sequence is the C-rich sequence 5′-CCGC-3′, which more frequently nicks the complementary strand of the sequence shown but does generate double-strand breaks (135). The modified T4 HMC DNA is resistant to cleavage, so that EndoII serves to restrict “foreign” phage or host DNA. Properties of EndoII have prompted the suggestion that the free DNA ends it generates would be recombinogenic for acquisition of DNA into the T4 genome (134). DenB (EndoIV) also cleaves cytosine-containing DNA and not the phage HMC DNA, but there is still only limited information available on its specificity (140).

In addition to the protection afforded by the HMC in T4 DNA, the phage encodes other nucleotide modification enzymes that act postreplicatively and protect the DNA. The dam-encoded DNA-(N6-adenine)methyltransferase of T4 belongs to the α group of GATC family of DNA methyltransferases. Using S-adenosylmethionine as the methyl donor, it modifies adenine in GATC and in the T4 sequence GAT HMC (140, 267). This modification protects otherwise unmodified T4 DNA from a restriction system of P1 phages.

The α-gt- and β-gt-encoded enzymes (α- and β-glucosyltransferases, respectively) modify the T4 HMC residues to the extent that there is ca. 70% in α-glucose linkage and 30% in β-glucose (reviewed in reference 139). Restriction of nonglucosylated T4 DNA (strains defective in gt activity) led to the discovery of the host restriction enzymes RglA and RglB, which were then recognized as broader systems for modified cytosine restriction and hence were renamed McrA and McrBC, respectively (139). The enzymes do not distinguish between mC and hmC modified DNA. mcrA of E. coli K-12 resides in a cryptic prophage-like element, e14, that is not present in all E. coli strains (37), whereas mcrBC resides at an unlinked location adjacent to the mrr and hsd restriction systems. T4 provided an important entry into unraveling the genetic organization and specificities of these enzymes. The presence of Mcr enzymes in E. coli or other bacterial hosts may have provided selective pressure to maintain the different DNA-glycosylating enzymes of T-even phages. In addition, the T4 arn gene encodes an antirestriction endonuclease that inhibits the host McrBC (RglB) enzyme (533).

Exclusion of T4 rII mutants by E. coli lambda lysogens is discussed above (see “Lysis and lysis” inhibition).

As detailed above (see “mRNA and tRNA turnover”), another cryptic DNA element of certain E. coli strains, prr, encodes the PrrC protein that excludes mutants deficient in T4 RNA ligase/polynucleotide kinase. The PrrC RNA endonuclease is activated by the small T4 Stp protein to cleave the anticodon loop of an essential host lysine tRNA (515, 1021). T4 RNA ligase (rnlA or gene 63) and polynucleotide kinase (pseT) can repair this damage, but in the absence of RNA ligase the cleavage of the tRNA is lethal to T4 protein synthesis. Intriguingly, the prrC gene is located between three genes of a type IC restriction cassette. The corresponding proteins are thought to inhibit PrrC RNase activity in uninfected cells.

Two additional exclusion mechanisms involving T4 can be cited. Phage P2 lysogens exclude T4 by two mechanisms: the Tin protein poisons gp32, which is essential for all T4 DNA replication and recombination (794), and the P2 Old protein degrades T4 and lambda DNA from ends, nicks, and gaps unless they are protected by specific proteins (125). It seems more than likely that many other cell-, phage-, and plasmid-encoded mechanisms of T4 exclusion remain to be discovered.

PREDICTED INTEGRAL MEMBRANE PROTEINS

One approach to exploring the function of the many uncharacterized T4 ORFs is to determine the cellular localization of their products. A number of early T4 studies used cell fractionation and gel electrophoresis to identify membrane-associated phage proteins during infection (reviewed by Harper et al. [385]). There is evidence that the cell envelope continues to be synthesized after infection. The optical density of the infected culture continues to increase substantially under a variety of growth conditions. Freedman and Krisch (291) demonstrated ongoing cell enlargement coupled with gradual arrest of cell division after infection of E. coli B in M9 by using a combination of Coulter Counter and dry-weight measurements. The rate of incorporation of diaminopimelic acid remained equal to that of uninfected cells for at least 50 min after infection, supporting the presence of ongoing growth and repair of the peptidylglycan layer. The total phospholipid content continues to rise as rapidly in T4 infected cells as in the uninfected control (as reviewed in reference 385). The rate at which phosphatidylglycerol is synthesized actually increases markedly after infection, while that of phosphatidylethanolamine diminishes, suggesting some changes after infection in basic membrane properties. Synthesis of host membrane proteins appears to be shut off along with that of other host proteins, as observed on two-dimensional gels (189), implying that most new protein in this expanded membrane is either phage encoded or the result of continued processing of already-synthesized host membrane proteins (385).

In recent years, an alternative (bioinformatic) approach to exploring protein function has been developed on the basis of primary sequence data. Computer programs are now available that use various algorithms to predict localization of proteins to the membrane or periplasm. Boyd et al. (105) optimized a statistical approach to determine the probability of an individual protein being integrated into the bacterial inner cell membrane. The calculation of these so-called MaxH values gives two very distinct peaks for proteins from a variety of organisms. These calculations were carried out for the complete set of T4 proteins and ORFs (D. Boyd, E. Thomas, and E. Kutter, Evergreen Int. Phage Biol. Meet., abstr. 11, 1998), using normalization constants determined with the training set of known E. coli proteins (105). MaxH values above 1.505 are considered to have a >50% probability of being integral inner membrane proteins. Using this approach, two very distinct peaks are also obtained for T4, with 15 T4 proteins predicted to be integrated into the inner membrane with a probability of over 99%. Three proteins are given a probability of 45 to 95%, three are given a probability of 1 to 16%, and the rest are given probabilities generally well below 0.001%.

Additional programs that predict cellular localization have been applied to all T4 proteins (Kutter, unpublished). TMPred (www.ch.embnet.org/software/TMPRED_form.html), SignalP (www.cbs.dtu.dk/services/SignaIP/), SOSUI (sosui.proteome.bio.tuat.ac.jp/sosuiframe0.html), and PSORT (psort.ims.u-tokyo.ac.jp/) variously predict the presence of transmembrane domains; the presence of leader sequences, their cleavage sites and lipid modification sites (lipoproteins); and whether the protein should be localized to the cytoplasm, cytoplasmic membrane, outer membrane, or periplasm. We summarize the major conclusions from these analyses in Table Table6.6. In most cases the programs agree, but there are some interesting exceptions.

TABLE 6.
Potential T4 membrane proteins and their cellular locations

Integral Membrane Proteins of Known Function

Some of the high-scoring proteins from the predictive programs have long been considered to be membrane proteins. For example, Imm, holin (t), rI, and Ac have recognized physical and functional cell envelope associations. The additional proteins having predicted membrane-related properties either are encoded by uncharacterized ORFs or are proteins that have not previously been considered to be membrane associated. We first summarize the predicted properties of the better-recognized T4 membrane proteins.

The immunity protein, Imm (83 aa) plays a primary role in the exclusion of superinfecting phage (3, 1113). Various programs predict it to be a typical membrane protein, with two transmembrane (TM) domains and its N and C termini probably external to the cell. However, PSORT and SignalP both suggest that Imm is periplasmic or possibly in the outer membrane. The site of localization needs to be determined experimentally; any of the three sites are consistent with its known function. The gene adjacent to imm encodes Imm.1 (125 aa), which is predicted by PSORT to be a lipoprotein with equal probability of being in the inner or outer membrane; it may well work together with Imm in superinfection exclusion.

The T4 holin (218 aa, encoded by gene t) is predicted to have a single TM domain, but with an unusual charge distribution for a membrane protein. It has very different properties from other known phage holins, as extensively reviewed (886, 1145). Analysis of t mutants with a rapid-lysis phenotype (rV mutants) indicates that various segments throughout much of gpt are involved in the phenomenon of lysis inhibition (discussed above) (236). Biochemical confirmation has been provided that gpt has a single N-terminal transmembrane domain and that the bulk of the protein lies in the periplasm (886, 887). Thus positioned, T4 holin apparently receives a signal that additional phage are trying to enter the already-infected cell; lysis inhibition is thus an effective strategy to promote exclusion of other phages and optimal accumulation of T4. This extra role for gpt in receiving the signal for lysis inhibition may explain why it is larger than other holins.

gp rI (97 aa), the other T4 product required for lysis inhibition, is the apparent signal transducer (851, 888). Cloned rI can produce lysis inhibition in lambda-infected cells if the lambda holin gene has been replaced by the T4 t holin gene. It is classified by both PSORT and TMpred as an inner membrane protein with one TM domain at residues 1 to 22, but its MaxH value of 1.40 puts rI slightly below the threshold of membrane proteins, with a probability of 10−7 of being in the inner membrane. The SignalP program was used to predict that gprI is a periplasmic protein (851), and SOSUI assigns the one potential TM domain as a signal peptide. The uncertainty revolves around whether or not this signal peptide is cleaved. Unpublished experiments (E. Ramanculov and R. Young, personal communication) were inconclusive in determining whether it is in the membrane or in the periplasmic space, due to the extreme instability of the rI protein; clearly, more experimental work is needed.

Ac (51 aa) confers resistance to acridine dyes, and its gene served as an important genetic marker in early phage crosses (894). It is a clear, if not typical, membrane protein according to MaxH and SOSUI analysis. However, PSORT suggests that the potential signal peptide is cleaved so as to add an N-terminal lipid and classifies it as a lipoprotein, giving it equally high probabilities of being in the inner or outer membrane. SignalP suggests it may be cleaved between residues 18 and 19.

Two baseplate proteins, gp7 (1032 aa) and gp29 (590 aa), have MaxH values predicting a 99.6% and 96% probability, respectively, of being integral membrane proteins. PSORT, SOSUI and TMPred all predict that gp7 has a single C-terminal TM domain and that gp29 has a pair of TM domains in the middle (Table (Table6).6). As mentioned above, the baseplate is assembled on the membrane. gp7 and gp29 are involved in initiating wedge and hub assembly, respectively, and gp29 later becomes the tail-length calibrator. The baseplate remains attached to the inner cell surface (via 300Å fibers from the six corners) throughout tail morphogenesis and the start of lysis (1003), and antibody studies have localized gp7 to the outer corners of the baseplate. This location is consistent with the C-terminal region of gp7 being the observed fibrous attachment structures; at 1,032 aa, gp7 is the second largest T4 protein, comparable in size to the two main tail fiber proteins.

Hypothetical Proteins with Predicted Cell Membrane Associations

The T4 genome has three apparent gene clusters that encode predicted envelope proteins (Table (Table6).6). One of these lies between rIIB and 52, a region of very short genes and ORFs, including ac, where it was difficult to determine gene and ORF assignments using standard computational methods. Other proteins encoded by this region and predicted by MaxH to be membrane proteins include 52.1 (51 aa, N inside the cell), Ndd.2a (40 aa, C inside but atypical in its structure), Ndd.4 (42 aa, N inside), and possibly MotA.1, Ndd3 (26 aa), Ndd.5 (32 aa, N inside), and Ndd.6 (28 aa, C inside). Ndd.2a, Ndd.6, and MotA.1 are characterized by PSORT as probable periplasmic/possible outer membrane proteins, while PSORT gives Ndd.2 and Ndd.5 over a 90% chance of being in the outer membrane.

The experimental work of Harper et al. (385) suggested that at least two genes in the ac region are required for the stimulation of phosphatidylglycerol biosynthesis following T4 infection; one of them is required for ongoing phospholipid synthesis after infection. Their identity has yet to be determined, but some of these predicted membrane proteins may well be involved. Ndd (for “nuclear disruption deficient”) has often been assumed to be a membrane protein, due to its observed role in binding the bacterial DNA to the membrane. However, its MaxH score is only 1.22, and PSORT and SOSUI localize it to the cytoplasm. Nucleoid binding may actually involve the combined function of multiple proteins from this transcriptional unit, which extends from ndd.4 through motA.1.

The second cluster consists of significantly larger predicted membrane proteins and is located in the e (lysozyme)-tRNA region, the general region where the still-unpositioned “star” plaque mutants stI and stII, affecting lysis timing, were mapped (583, 1208). gpe.3 (120 aa) and gpe.4 (130 aa) both clearly have two potential TM domains, with N and C inside the cell; gpe.4 is one of the few T4 proteins that looks like a typical membrane protein. PSORT calls the N-terminal helical domain of gpe.3 a cleavable signal peptide, which would leave only one transmembrane domain in the final protein. gpe.2 (102 aa) is predicted to be an integral inner membrane protein, although it is otherwise very hydrophilic. gptRNA.4 (61 aa) is also predicted by all four programs to have two transmembrane regions.

The third possible cluster is a compact eight-gene operon that starts with cd.3. PseT.3 (117 aa, with an apparently uncleavable signal peptide TM) is encoded in this cluster and is predicted by all programs to be an integral membrane protein. The adjacent ORF, pseT.2 (99 aa), is also predicted by SOSUI (but not the other programs) to encode a membrane-associated protein, with a potential signal peptide at residues 1 to 21. PSORT, SOSUI, and TMPred all suggest that the Cd.3 protein may also be in the inner membrane, although the scores are barely above the cutoff in each case.

Three other isolated ORFs are also generally predicted to encode integral membrane proteins. These are 47.1 (46 aa), 55.8 (70 aa, very hydrophobic) and NrdC.7 (133 aa, with a cleaved signal peptide as well as one C-terminal TM domain). ORF 47.1 overlies a middle promoter and encodes a protein of only 46 aa. Because gp47.1 has a correlation coefficient of only 0.30, it was earlier dropped from the list of probable T4 proteins. It has been reinserted on the basis of this analysis. It could function as the membrane anchor for the gp46/47 nuclease earlier reported to be a membrane protein (345, 731).

Missing Membrane-Associated Proteins

Notable by their absence from this list of predicted integral membrane proteins are several proteins that were classified as membrane associated on the basis of early experimental work (reviewed in reference 385). Huang (446) performed the most extensive gel analysis to date of proteins that are enriched in the membrane fraction following differential centrifugation. Most that were observed have not yet been identified genetically. The MaxH and PSORT scores and other predicting programs all give zero integral membrane probabilities for most known proteins that were identified as membrane associated in those studies, including gprIIA, gprIIB, Ndd, and gp46. gp52 has a slight potential for one TM domain near the center but is still classified by all of the programs as cytoplasmic. It is important to test more carefully the connection that these proteins have to the membrane, a relationship that was observed by several groups. The current analysis would predict that they are likely to be bound peripherally, perhaps through other proteins, lipid, or DNA. Some of the small membrane proteins cotranscribed with 46, ndd, and 52 could be involved in such attachments, as suggested above.

The use of multiple programs provides complementary insights when using predictive algorithms. Experimental work is required to assess the significance of the predictions by the various programs for TM domains and other membrane associations for these T4 proteins. However, the analysis suggests a starting point for determining the functions of a number of otherwise uncharacterized ORFs and should aid the study of cell expansion and membrane changes during T4 infection. The clustering of many predicted membrane-associated proteins is consistent with the organization of other functional groups of T4 genes.

EVOLUTIONARY PERSPECTIVES: T4 PROTEINS AND THE GENOME

Extensive functional, mutational, and structural data on a number of the T4 proteins provide an excellent framework for advancing the study of protein evolution. Many of the DNA metabolism and replication enzymes of T4 have orthologous proteins represented in all domains of life, which is why the biochemical and structural studies of T4 proteins have been so broadly relevant. Growing knowledge about specific genes, complete genomes, and the proteomes of at least a few T4-related bacteriophages are beginning to make possible comparative genomics studies that impact our understanding of the well-studied T4 systems and broaden our perspectives for other organisms. In the sections below, we briefly summarize the reported structural and evolutionary relationships of T4 proteins and provide some evolutionary reflections on the T4 genome and that of its relatives. A more thorough discussion of the evolutionary relationships among T4-related phages will appear elsewhere (E. Thomas, F. Zucker, and E. Kutter, unpublished data).

T4 Protein Structures

Structural studies of T4 proteins began with the crystallization and three-dimensional structure determination of gpe (lysozyme) (705, 1158). T4 lysozyme is an excellent example of structural analysis and targeted amino acid replacements used hand-in-hand to unravel an enzyme's catalytic properties and protein conformation (594, 1193). Solving the structure of the T4-related RB69 phage DNA polymerase (1146), when the T4 enzyme has been refractory to crystallization, has permitted a full appreciation of the structural and catalytic effects of the numerous available mutations in T4 gene 43 (DNA polymerase) (40, 507, 827, 906). Currently, the structures of 23 T4 proteins, protein domains, and protein complexes are deposited in the Protein Data Bank (Table (Table7;7; http://www.rcsb.org/pdb/). In addition to protein structure studies, an RNA-folding model (pdb entry 1SUN) predicts how the 3′-terminal domain of the RNA stabilizes the intron core (468, 730). Each of these structures provides a framework for functional and evolutionary analysis of the respective protein or molecular machine in which it participates. Evolutionary relationships between macromolecules, whether phage or cellular, will be fully appreciated only in the context of their structures, so that the yield from structural studies of additional T4 proteins would appear to be high.

TABLE 7.
T4 proteins in the structure database

Orthologous T4 Proteins

T4 proteins involved in nucleotide and nucleic acid metabolism typically show sequence similarity to functionally related enzymes of other organisms (69). Proteins that have orthologs in the database are often members of multientry clusters of orthologous groups (COGs) curated at the National Center for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/COG). The T4 genome page (NC_000866) provides access to each protein and its respective COG. Proteins involved in DNA transactions (UvsX, Topo II, NrdD, Td, and many others) are present in organisms across the phylogenetic tree and have dozens if not hundreds of entries. However, only 28 of 274 T4 proteins can be grouped into clusters of related phage proteins. These relationships among viral and phage proteins, including proteins of T4, are now cataloged by NCBI at a dedicated website (http://www.ncbi.nlm.nih.gov/PMGifs/Genomes/crp_start.html).

One of the most interesting and potentially instructive examples of an orthologous protein is thymidylate synthase (td or TS). A number of stretches of amino acids are highly conserved between Bacteria, Eucarya and T4, facilitating precise alignment and analysis; these are indicated in red on the crystal structure of the T4 enzyme shown in Fig. Fig.1010 (also see pdb 1TIS). The two stretches indicated in yellow are totally different between the T4 enzyme and all other thymidylate synthases; these regions are largely hydrophobic in T4 but hydrophilic in other members of the family. They lie on the surface of the enzyme, where presumably they are involved in the interaction between thymidylate synthase and other enzymes of the nucleotide synthesis complex described above. When these two segments are excluded and the core regions are used for alignment, the phylogenetic relationship shown in Fig. Fig.1111 is obtained. The tree suggests that the T4 enzyme branched off somewhere before the split between Eucarya and Bacteria. The apparently ancient branch point is not just due to faster evolution of viral proteins than of proteins of their hosts, since, for example, herpesviruses appear to branch off much later in the Eucarya lineage, just before the separation between the human and rat-mouse lines. Also, T4 TS has several regions that are characteristic of the eukaryotic enzymes, intermixed with others that seem to be unique to the bacterial sequences. T4 TS also has one sequence near the N terminus that is otherwise unique to archaeal thymidylate synthases, which are sufficiently different from those of bacteria and eukaryotes that they are more difficult to align unequivocally. Figure Figure1111 also shows the distant relationship between thymidylate synthases and T4 HMase (gp42; also see pdb 1B5D). This is not too surprising since both enzymes catalyze the transfer of methyl (or hydroxymethyl) to the same position on a pyrimidine monophosphate (dUMP and dCMP, respectively).

FIG. 10.
Structure of T4 thymidylate synthase. The T4 sequence was aligned with other available thymidylate synthases, with the invariant regions colored in red and the regions in which the T4 enzyme is different from all others colored in yellow. The latter regions ...
FIG. 11.
Phylogenetic tree of thymidylate synthases and deoxynucleotide hydroxymethylases. All protein sequences were obtained from the public databases. Alignment and tree construction were done by the methods of Feng and Doolittle (271).

The T4 dihydrofolate reductase and the three topoisomerase II components (gp39, gp52, and gp60) also appear to have diverged before the separation of prokaryotes and eukaryotes. This is seen in both the clade patterns and the clear interspersion of sequences uniquely conserved among eukaryotes between ones that are characteristic of prokaryotes.

Other T4 proteins are more closely related to bacterial proteins. These include thymidine kinase (tk), DNA adenine methylase (dam), and the ribonucleotide reductases. The T4 anaerobic NTP reductase (NrdD) and its copeptide, NrdG, are most closely related to the E. coli proteins; however, even these two enzymes appear to have diverged from their host counterparts well before the separation between the Haemophilus influenzae and E. coli enzymes.

T4 DNA polymerase aligns with the B family of DNA polymerases, which includes archaeal, eucaryal, bacterial, and viral enzymes (273). Included in this group are pol II enzymes of γ-proteobacteria (such as E. coli), involved in DNA repair, and DNA polymerases of Saccharomyces, herpesvirus, and chlorella virus. Interestingly, the T4 DNA polymerase is most closely related to polymerases of the archaeal halophile Halobacterium sp. and two of its viruses, HF1 and HF2 (273). These relationships also emerged in the crystal structure of the DNA polymerase of the T4-related phage RB69 DNA (507, 1146) and have been functionally confirmed. A mutation introduced into yeast DNA polymerase (POL3) on the basis of the mutator properties of an altered T4 DNA polymerase gave a yeast mutator phenotype (370). Moreover, gp44, a subunit of the DNA polymerase clamp loader, is orthologous to eukaryotic replication factor C, as discussed above (see “DNA metabolism, replication, recombination, and repair”). Its highest-scoring homology is 29% identity, over its entire 319-residue length, to the Archaeglobus fulgidus replication factor.

Primary sequence homologies to eukaryotic viruses are also observed. For example, T4 DNA ligase (gp30) is most homologous to the DNA ligase of the African swine fever virus (25% identity over a conserved region of 229 of its 487 aa). It also shares smaller conserved regions with archaeal DNA ligases (such as 27% identity over 154 aa for Methanobacterium thermoformicicum). Two T4 proteins have a particularly interesting homology to an insect viral protein. PseT (the 5′ polynucleotide kinase-3′ phosphatase) and RnlA (gp63 RNA ligase) are similar in amino acid sequence to the two halves of ORF86 in the Autographa californica nuclear polyhedrosis virus (246). Together, rnlA and pseT look somewhat like the tRNA splicing machinery in eukaryotes. The A. californica nuclear polyhedrosis virus ORF86 protein has been named Pnk/Pnl to reflect its relationship to the T4 enzymes and its motifs that are characteristic of polynucleotide kinase and RNA ligase. There is generally no need for tRNA splicing machinery in T4, since its tRNA genes contain no introns. However, the ligase and kinase activities are both required in host strains with the restriction system carried by the cryptic DNA element, prr (see above) (515).

Paralogous Genes in the T4 Genome

The T4 genome contains a few apparent duplications that have evolved into separate functional genes. These include modA-modB (781) and genes 9-10 and 23-24 (225), as well as a duplication of lysozyme (gene e) found inserted into the baseplate protein gp5 (787). This lysozyme insertion, although present in gp5 of coliphages RB49 and RB69, is not seen in gp5 of the Vibrio phage KVP40 (Miller et al., submitted). Duplications in the T4 genome have also been explored by evaluating structural similarities in proteins with low-level sequence homologies (T. Kawabata, K. Nishikawa, F. Arisaka, and E. Kutter, unpublished data). Potential duplications were identified in the pairs of proteins encoded by the adjacent genes 26-51, rnh-34, 49-nrdD, dexA.1-dexA.2, and tk.1-tk.2. FASTA alone indicated relationships between gpe.3 and gpe.4 and between gpAlt.-1 and Alt.-2 and the N-terminal region of Alt, the latter apparently reflecting an ancient duplication followed by insertion of a new internal start codon to generate this pair of ORFs. Noted similarities were also seen between gp34, gp37, and gp12, all of which form trimeric β-helix fibers. Internal repeats were seen in gp34 (40 aa, 7 X), gp12 (25 aa, 5 X), hoc (94 aa, 3 X) and gp46 (100 aa, 2 X), where X indicates the number of times each motif is repeated.

A Glimpse at Genome Diversity and Evolution in T4-Type Phages

Bacteriophages may well be the most numerous living entities on Earth; about 10 times as many phages as bacteria have been seen in ocean samples, leading to a total estimate of about 1032 phages on Earth (62, 1184). There is interest in how viruses arose, how they acquire their special properties and genes, and how they relate to each other and to cellular genomes.

Botstein (100) presented evidence that lambdoid phages are a mosaic of ordered sets of modules, each of which may have come from a particular host, plasmid, or other phage. This concept has since been extended to other temperate phages, and a lambdoid “supergroup” seems to extend even into gram-positive bacteria (128, 149, 209, 400). For example, L5- and ψM1-like phages, which infect mycobacteria and Archaea, respectively, and are members of the Siphoviridae family, show a distant but still detectable similarity in their genome organization with lambdoid phages (209). Another genus of Siphoviridae, the c2-like Lactococcus phages, differs a good deal from the lambda pattern of structural gene organization but could still be aligned with the lambda-like Lactococcus phage sk1 when allowing for two genome rearrangement events (117, 118).

Nonetheless, “modular mosaicism” does not appear to be an appropriate characterization for the genomes of T4-like phage. Genome sequence surveys of T4-like phages (210, 700, 702, 919, 1067, 1069) suggest that T4 and its relatives are largely in a group by themselves, undergoing few exchanges with other phage families. Sequence homology is observed between the receptor-binding region of the tail fibers of the T-even group and other phages, apparently reflecting the selection for new receptor-binding capabilities and the special recombinogenic properties of this region (1067). BLAST analysis between T4 and P1 proteins (M. Lobocka and M. Yarmolinsky, personal communication) reveals some homologies in the tail tube, baseplate, and two DNA metabolism enzymes. Nonetheless, there is no evidence for ongoing exchange events between T-even phages and other phages that involve entire gene cassettes or modules; exchanged segments are usually the size of single genes or smaller. The high frequency of recombination observed for T4, its lytic developmental program, and the presence of multiple promoters throughout the genome allow for many independent exchanges of smaller genome segments, apparently precluding extensive selection for large modular genetic units.

The DNA endonucleases or “homing enzymes” in group I introns of T-even phage could afford one mechanism for gene dissemination. However, Edgell (251) discusses reasons why this appears not to occur. The related T4 Seg and Mob endonucleases may also either disseminate or exclude targeted regions of the phage genome (51, 335). The presence in phages of gram-positive bacteria of ribonucleotide reductase genes (bnrdE and bnrdF) with T4-like group I introns (626) may suggest that introns and genes with introns (see the discussions above on homing endonucleases) can be transferred between phage of major phylogenetic divisions.

Phages with T4 morphology have been isolated from a variety of sources throughout the world: sewage plants, coastal and offshore seawater, zoos, and diarrhea patients in the former Soviet Union and the United States (8, 247, 379, 596, 703, 946, 1233). Members of the family have been found infecting several different gram-negative bacteria (8). The T4-like phages infecting a range of host genera generally show conservation in gene order and protein sequence for the essential units—capsid and tail structures and DNA replication proteins. Since T4 has until very recently been the only fully sequenced member of its myovirid subgroup, with just short genomic regions of sequence data obtained from other phage by PCR analysis or localized cloning (485, 748, 919, 1217), the evolutionary relationships of only a few specific genes (e.g., 56 and the head and tail genes) have been studied in detail (777, 1069).

During the completion of this review, progress on genomic sequencing of T4-type phages has been achieved. The genomes of phage that infect γ-proteobacteria (E. coli phage RB69 and RB49; Aeromonas phages Aeh1, 44RR2, and 65; Vibrio phage KVP40; Acinetobacter johnsonii phage 133 β-proteobacteria), (Burkholderia cepacia phage 42), and cyanobacteria (Synechococcus phage S-PM2) (210, 379, 700, 1069; H. Krisch, J. Karam, et al., personal communication; Miller et al., submitted) are all under study. Many have dsDNA genomes similar in size to T4, while some, such as KVP40 (Miller et al., submitted) have longer heads, filled by substantially larger genomes (e.g., 245 kbp). For these different T4-like phages, ClustalW and neighbor-joining bootstrap analysis of capsid and tail tube proteins led to similar phylogenetic trees with relationships paralleling those of the host bacteria (379, 1069).

Current sequencing projects reveal that the genomes of some T4-type phage infecting E. coli are arranged much like that of T4 (such as RB69; see http://phage.bioc.tulane.edu), although group I introns, seg genes, and other characterized nucleotide metabolism genes are absent. For other T4-like coliphages (such as RB49), there are yet fewer of the “nonessential” T4 genes and more hypothetical, uncharacterized ORFs (210). For RB49, conservation of the DNA replication and viron structural proteins is most evident. A related situation is seen for the Vibrio phage KVP40. The DNA replication and structural proteins most closely align with those of T4 (ca. 35 to 70% similar), but this represents only about 20% of the ORFs, with more than 60% still having no characterized function (Miller et al., submitted). The same pattern was observed in the genome sequence of Bacillus phage SPβc2; 75% of its predicted ORF products have no significant homologies to proteins in the databases (625). One of the more extreme examples to date is the 280,334-bp genome of Pseudomonas aeruginosa myoviridae phage phiKZ, with only 59 of its 306 ORF products aligning with proteins of known function in the database (727); fully 80% of the proteins it encodes appear not to have been characterized in any organism. It seems likely that the more conserved DNA replication and virion genes of T4-like phages are the ancient genes. The few complete phage genome sequences that are available, which can have 50 to 80% of the ORFs as unique, suggest the presence of a separate, more variable group of genes in each genome. However, our overall view of phage genomes is still very limited, where the small number of BLAST hits with phage proteins in part reflects the paucity of complete phage genome sequences in the databases.

No phages morphologically identical to T4 have been identified as infecting gram-positive bacteria. Bacillus subtilis phage SP01, containing dsDNA (ca. 140 kbp) with HMU in place of thymine, somewhat resembles T4 (47-nm-diameter head and 142-nm-long sheathed, contractile tail) and has several DNA metabolism and replication enzymes similar to those of T4. The sequenced dsDNA genome of the temperate Bacillus phage SPβc2 (accession no. NC_001884 and AF020713; 134,416 bp) (625) has a few DNA metabolism enzymes that are present in T4, and its ribonucleotide reductase genes harbor the T4-like group IA2 introns (624). Clearly, genomic sequences of large lytic phages infecting gram-positive bacteria and others from across the phylogenetic tree are of great interest. The return on phage genome sequencing would appear to be highest for comparative functional and structural biochemistry on the individual gene products and for new protein and RNA resources for biotechnology, such as novel antimicrobials, therapeutics, and diagnostic reagents.

OUTLOOK

T4, with its legions of investigative disciples over the last 50 years, has provided us with a beautifully integrated system of biological machines and networks (506, 697). The otherwise elaborate biochemical perspective on the fully sequenced T4 genome provides a vast resource for phage genomics and the future of phage biology. Among the large, ubiquitous group of tailed, T4-like phages found on Earth (8), phage T4 has been the most extensively studied. T4 biology will “bootstrap” us to the recognition of similar biochemical processes in related phage while identifying genes and proteins that are novel to each. It is already clear from emerging genome sequences that although some of the uncharacterized ORFs in T4 are shared in other phages (i.e., RB49, RB69, and KVP40), each has a relatively large proportion of individually unique ORFs. Just in the past year, the identities of uncharacterized T4 ORFs have been revealed: gene 69 (segF) and ORF 32.1 (segG) encode DNA endonucleases (51, 655), ORF e.1 (nudE) encodes a Nudix hydrolase (1204), and ORF 24.1 (rnlB) encodes a second T4 RNA ligase related to the RNA-editing enzymes of trypanosomes and those present in sequenced Archaea (426). T4 will be a handy genetic and biochemical tool for detailed studies of their respective enzymatic activities. As with any fully sequenced genome, strategies (beyond BLAST alignments) are needed to explore the function of the novel phage ORFs. T4 should be a sound model for dissecting the emerging genome sequences of related phages while itself continuing to provide new insights into gene function and phage metabolism with relevance across phylogenetic domains.

Many of the unresolved problems in T4 biology reflect the subtlety of the process or the demands on the researcher for sample preparation, timing, or control of growth conditions. We still do not fully understand the process of DNA entry during infection, the very early shutoff of host gene expression, and the relevance or mechanism of T4-directed disruption of the host nucleoid. Moreover, the effects of hydroxymethylated and glucosylated cytosines in T4 DNA on DNA-protein interactions important for transcription, DNA replication recombination, repair, and restriction remain to be determined. To achieve this, the availability of T4-like modified phosphoramidites and of α and β glucosyltransferases for synthesis of modified DNA would be a major asset in addressing the recognition of early, middle, and late promoters by variously modified RNAP and the relevant activator proteins. Similarly, the potential roles of ModB modifications of the host translation proteins and the genetically still unidentified ribosomal alterations and the role of the membrane in transcription, replication, and capsid assembly are all in need of additional biochemical studies.

One of the more elegant aspects of T4 biology has been the elucidation of the assembly mechanism of its supramolecular structure. To construct such a huge, complicated and intricate structure, a number of intriguing molecular tricks have evolved, such as a scaffold, DNA-packaging apparatus, a ruler molecule, and phage-encoded molecular chaperones (e.g., gp31). Details of this process are still probably hidden in the genome. Additional study on the high-resolution structure of the particle will eventually elucidate how a series of structural changes (conformational change of the baseplate, contraction of the tail sheath, and DNA ejection) take place at atomic resolution.

Practical applications of phage and phage gene products should continue to emerge. In an era of increasing bacterial antibiotic resistance, there is renewed interest in the therapeutic applications of phage in the treatment of infectious disease (37a, 83, 141, 725, 866, 1052a; www.evergreen.edu/phage). It was Delbrück and the initial American phage group who selected three of the seven virulent coliphages—T2, T4, and T6—from among early, largely “therapeutic” isolates. Even today, one of the best sources of T-even-like phages is the stools of patients recovering from dysentery (L. Gachechiladze and H. Brussow, personal communication). Specific proteins, phage lysins in particular, have been proposed as useful enzymes for killing troublesome bacteria (66, 759). Recently, purified PlyG lysin (an N-acetylmuramoyl-l-alanine amidase), produced by gamma phage of Bacillus anthracis, was shown to effectively kill the bacterium (967). T4 and its relatives will probably yield novel products that target various cellular processes, inhibiting or killing their host bacteria.

Many of the major enzymes of molecular biology came onto the scene with T4, yet there are few laboratory reagents that derive from other phages beyond the well-studied isolates. There is every reason to expect that enzymes with unique catalytic parameters will emerge from genome sequences of other phages.

Phage are also an excellent teaching tool. They are easy to work with, so students can learn the simple methods required and get meaningful results quite easily. Phage research also calls for integrating broad areas of microbial physiology, biochemistry, biophysics, genetics, and molecular biology. The analysis presented here of the T4 genome and its relationship to phage biochemical processes, ecology, and evolution is based on the work of many students of many ages and countries. One can only hope that the scientific community will continue to take advantage of the historically large investment of intellectual and fiscal resources committed to T4 and will continue to explore the vast, wonderful world of phage biology.

TABLE 1.
Continued

Acknowledgments

We express our appreciation to the entire T4 community for their help through the years in the assembly and analysis of the T4 genome sequence. Special thanks go to Burt Guttman, Tsotne Djavachishvili, Nino Mzhavia, Elena Marusich, Tom Stidham, Elizabeth Thomas, Raul Raya, and Judy Cushing at Evergreen; to Tim Dean at NC State; to Vadim Mesyanzhinov and his students in Moscow; and to Tim Hunkapillar, Frank Zucker, Mark Borodovsky, Tom Schneider, Fred Blattner, and Gary Stormo for various computational collaborations.

Work at Evergreen was supported by a series of NSF grants from the Microbial Genetics, Biological Database and Collaborative Research at Undergraduate Institutions (CRUI) programs. G.M. thanks the National Science Foundation and the Vanderbilt Ingram Cancer center for support. W.R. thanks the DFG and the MBF NRW for many years of financial support, past group members of Molecular Genetics at the Ruhr-University, and the groups of R. S. Nivinskas (Institute of Biochemistry, Vilnius, Lithuania), P. S. Freemont (Imperial Cancer Research Fund, London, United Kingdom), S. Moréra (Laboratoire d'Enzymologie et Biochemie Structurale, Gif-sur-Yvette, France), and R. R. Schmidt (Fachbereich Biochemie, University of Konstanz, Konstanz, Germany) for their cooperation in unveiling the secrets of T4.

Footnotes

Dedicated to the memory of Gisela Mosig, our friend, colleague, and mentor.

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