NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

Cover of Madame Curie Bioscience Database

Madame Curie Bioscience Database [Internet].

Show details

Recoding: Site- or mRNA-Specific Alteration of Genetic Readout Utilized for Gene Expression

, , , and .

A minority of genes in probably all organisms rely on “recoding” for translation of their mRNAs. Recoding can involve a proportion of ribosomes changing frame at a specific site in response to signals in mRNA, or some ribosomes reading through a stop codon to insert a standard amino acid or the 21st amino acid, selenocysteine. In other cases, ribosomes bypass a block of noncoding nucleotides present within an open reading frame. In several cases, recoding serves a regulatory function. Often there are distinct roles for both the product of standard decoding and the recoding product with which it shares amino terminal sequence. This review of the current state of the field includes a reassessment of the variety of mechanisms involved.

Since the genetic code and the mechanism of its readout were first elucidated, molecular biologists have found more and more evidence that “the code” and decoding are not written “in stone”. Some organisms have branched into an alternative meaning of particular codons. Even more fascinating is the ability of certain mRNA sequences to subvert the resident translational machinery. A number of genes, from viruses to higher eukaryotes, have evolved to exploit this latter type of translational plasticity in order to regulate their own expression. To distinguish these events from “standard” decoding, they are often referred to as “recoding”. Recoding events can be further subdivided into several distinctive categories: frameshifting, redefinition and hopping.


At defined shift sites in mRNA, ribosomes can be programmed to efficiently change to one of the two alternative reading frames for gene expression purposes. Commonly, there are stimulatory signals in mRNA distinct from the shift site that greatly increase the level of frameshifting at the shift site. As a result, ribosomes initiating at the same start codon produce two different protein products, one being the product of standard decoding and the other the product of a recoding event. Depending on the configuration of the open reading frames (ORFs) in an mRNA relative to the site of frameshifting, two outcomes are possible. If the stop codon of the new ORF (ORF2) is 3' of the termination codon of the original ORF (ORF1), the frameshifting product is longer (sometimes much longer) than the product resulting from standard decoding. Alternatively, if the stop codon of ORF2 is 5' of the end of ORF1, the frameshift protein product is shorter. Many more examples are known where the frameshift product is longer but that may be because of inherent biases associated with the discovery of frameshifting examples.


In redefinition, codon meaning is changed in an mRNA specific manner (as opposed to reassignments of the “universal” genetic code that are species- or organelle-specific). Specification of an amino acid by a “stop” codon results in the production of protein product, which is longer than the product of standard decoding. Most known cases of redefinition fall into this category, perhaps only due to the fact that the products of standard decoding and recoding, in this case, have usually very different sizes and therefore can easily be detected and distinguished by standard laboratory techniques. Encoding of selenocysteine by special UGA codons allows incorporation of this 21st amino acid thus extending the capabilities of the genetic code. Encoding an alternative amino acid by a sense codon could, in theory, result in the production of two proteins with the same number of amino acids but differing biochemical activities. Perhaps because of the technical difficulties of identifying such cases, no examples of this kind have been discovered.


In translational bypassing (hopping), a fraction of the translating ribosomes “skip” a portion of the mRNA without inserting any amino acid. Regular decoding is resumed some distance downstream. As with programmed frameshifting and redefinition, translational hopping occurs at defined sequences within an mRNA. Conceptually, bypassing can be described as translational splicing. Most known cases of bypassing involve heterologous expression or synthetic constructs where the ribosome hops over a single triplet codon and lands in-frame with the original reading frame. If the bypassed triplet is a sense codon, the protein synthesized is two amino acids shorter than the product of conventional decoding. When the bypassed triplet is a stop codon, the bypassing links two open reading frames to yield a longer polypeptide than the product of standard decoding. Bypassing needs not involve three, or multiples of three, nucleotides and so is frame independent. In the best-studied case of ribosomal bypassing, that is seen in the translation of T4 gene 60, translating ribosomes skip 50 nucleotides before resuming regular decoding. Because this links two separate ORFs, the resulting polypeptide is much longer that the product of standard decoding of gene 60 mRNA.

Examples of Recoding Events in Gene Regulation

As can be seen from the brief descriptions above, recoding presents great regulatory potential that is actively exploited in diverse organisms (reviewed in ref. 1). The ability to make two or more proteins from the same mRNA is sometimes very useful, especially for organisms that put a high premium on compact genomes. Not surprisingly, most examples of recoding events have been found in viruses and transposable elements. In addition, producing two proteins from the same mRNA allows the setting up of an exact stoicheometric ratio between them. In fact, in the majority of recoding events, the proportion of ribosomes that complete the nonstandard event is tightly set.

In most viruses and retrotransposable elements, the recoding event serves to link structural (e.g., retroviral Gag) and catalytic polypeptides (e.g., retroviral Pol or Pro-Pol) (reviewed in refs. 2 and 3). Standard decoding of retroviral genomic RNA typically produces only Gag protein (whose ORF is located 5' on the mRNA) but through recoding, Gag-Pol, or Gag-Pro-Pol, is produced as a single polypeptide.4 Viruses need many more molecules of structural proteins than catalytic ones. For this reason, in most of these cases, recoding frequencies are set in the range of 1 to 10% relative to standard decoding. The result is that most ribosomes synthesize just the structural subunits and only the minority, which undergo a recoding event, synthesize the polyproteins which are processed to yield the catalytic proteins. The frequency with which recoding events occur varies from one virus to another. So, in S. cerevisiae L-A virus, the −1 frameshifting required for production of its Gag-Pol counterpart occurs at 1.9%,5,6 the +1 frameshifting of S. cerevisiae Ty3 retrotransposon Gag-Pol mRNA occurs at 11%,7 and the human immunodeficiency virus −1 frameshifting required for the synthesis of Gag-Pol occurs at 0.7–7.3%.8,9 In each case, the efficiency of recoding has presumably evolved to suit the lifestyle of the virus or retrotransposable element. Experiments have shown that the ratio between Gag and Gag-Pol and therefore the efficiency of recoding can be crucial for retroviral and retrotransposon propagation. An increased or decreased ratio due to alterations in recoding efficiency hampers virus-particle assembly and infectivity of L-A and HIV viruses.10,11 It also leads to reduced transposition of Ty3.12

Another example where a recoding event (−1 translational frameshifting) sets up a fixed ratio between two polypeptide products is decoding of the E. coli dnaX gene,1315 which encodes two subunits of DNA polymerase III, τ and γ (Fig. 1). These two subunits are present in a ratio of 1:1 in the polymerase holoenzyme. The long form, τ, is synthesized by standard decoding. The short form, γ, shares its amino acid sequence with τ for the first two-thirds of the latter but has one additional amino acid at the carboxyl end. With the help of stimulatory signals in the mRNA,16,17 50% of translating ribosomes switch to the −1 frame at the “slippery sequence” A-AAA-AAG, two thirds of the way into ORF1. The ribosomes that shift frame decode one codon in the new frame before terminating at a now in-frame UGA stop codon to synthesize γ.1315 Because γ lacks two proteindomains domains of τ that bind to a replication protein called DnaB and the αϵΘ polymerase III core subunit respectively,18 the two polypeptides have different biochemical activities and, thus, the two subunits play different roles in DNA polymerase III.

Figure 1. Schematic representation of the −1 frameshifting in the expression of E.

Figure 1

Schematic representation of the −1 frameshifting in the expression of E. coli dnaX gene.

Many physiological conditions can alter the activity of the translational apparatus. Consequently, some genes have evolved to finely tune a recoding event to an autoregulatory pathway that affects the physiology of translation. Perhaps the best-studied example of the regulatory potential of recoding is the +1 frameshifting required for expression of E. coli release factor-2 (RF2).1924 RF2 is a translational release factor that mediates termination at the stop codons UGA and UAA (see also Ch.21 by M. Ehrenberg et al). RF2 protein is encoded by two partially overlapping reading frames. The first encodes only 25 amino acids. This peptide has no known biochemical function and is rapidly degraded. +1 ribosomal frameshifting at the last sense codon of the first ORF (ORF1), at the sequence CUU-U, results in the production of full-length functional RF2. Significantly, the stop codon of ORF1 is UGA, which is recognized only by RF2. A pause of translation at the shift site caused by low levels of RF2, contributes to +1 ribosomal frameshifting, thereby increasing synthesis of RF2 and closing an autoregulatory loop (Fig. 2). In this way, the frameshifting site “senses” the levels of RF2 in the cell.

Figure 2. The regulatory +1 frameshifting involved in the expression of E.

Figure 2

The regulatory +1 frameshifting involved in the expression of E. coli RF2.

Ornithine decarboxylase antizyme (antizyme) was first defined as a biochemical activity that inhibits ornithine decarboxylase and is induced in the presence of high concentrations of polyamines. Decarboxylation of ornithine is the first and usually rate-limiting step in the biosynthesis of polyamines in the cell. Polyamines have many documented biological activities, one of which is to affect the rate and accuracy of translation.25 Cloning of the first antizyme gene in mammals (rats) revealed that the ORF that encodes the biochemically functional portion of the antizyme protein (ORF2) does not contain an appropriate translation initiation codon.26 Instead, translation is initiated at an upstream partially overlapping ORF (ORF1) in such a way that +1 translational frameshifting in the overlap would result in the production of fully functional antizyme protein. Further analysis demonstrated that a ribosomal frameshifting event is involved and occurs at the very last sense codon of ORF1 on the sequence UCC-U.27 Importantly, in vitro and later in vivo experiments showed that elevated levels of polyamines increase the level of +1 translational frameshifting required for synthesis offunctional antizyme functional antizyme,2729 thus closing an autoregulatory loop. In this manner, the translational frameshifting on antizyme mRNA is a key component of the antizyme regulatory loop, serving as its sensor (Fig. 3). This mechanism is deduced to have evolved more than a billion years ago in the ancestor of modern day fungi, echinoderms, nematodes, insects, and vertebrates. It is amazingly conserved in all descendents that are known to possess antizyme homologs.30

Figure 3. The +1 frameshifting event involved in the autoregulatory expression of mammalian antizyme 1.

Figure 3

The +1 frameshifting event involved in the autoregulatory expression of mammalian antizyme 1.

Mechanisms of Recoding

Like all biological processes, translation is not error-free. However, translational errors due to misincorporation of the wrong amino acid or to a switch of translational reading frame are relatively rare; the most widely accepted estimate being 10−4 per codon.31,32 Although conceptually and often mechanistically similar, except for specification of selenocysteine, translational errors and recoding events are separated by a quantitative degree. The stimulatory signals for recoding have been evolutionarily selected and the product is utilized. These features put errors and recoding in qualitatively different categories. All recoding events share one mechanistic feature. In every case, the recoding event is in direct competition with standard decoding. Consequently, mRNA signals that perturb normal decoding stimulate the recoding event and vice versa. Recoding signals consist of several components. The first and most important signal is the actual site, within the mRNA, where recoding is initiated. These sites are made of three to seven nucleotides, and are necessary and sufficient for induction of the recoding event (except in the incorporation of selenocysteine). However, often they are insufficient for achieving the needed efficiency, and accessory cis-acting elements are utilized. In several cases, a single recoding site uses two or more different cis-acting stimulatory elements, placed both 5' and 3'.

Classification of cis-acting stimulators can also be made on the basis of the nature of the mRNA signal. In some cases, the cis-acting elements act through their primary sequence, in others, the stimulators act through a secondary structure they form. Of the limited number known, most that work through their primary sequence are 5' of the recoding site, although exceptions do exist. Such sequences can function either directly through their nucleotide sequence or through the nascent peptide they encode. Numerous cis-acting elements have been identified, however, the exact mechanism of their action is not well understood.

Despite their wide diversity, the great majority of recoding events can be grouped in only two major classes: “tandem slippage” frameshifting and ribosomal “P-site” events. To date, most examples of programmed translational frameshifting are of the −1 tandem slippage variety. Examples are known from retroviruses, coronaviruses, plant viruses, a yeast virus-like element, bacterial insertion sequences, bacteriophages and at least one bacterial cellular gene, E. coli dnaX.33 The tandem slippage model was first proposed by Jacks et al to explain the −1 frameshifting in Rous sarcoma virus.34 According to it, frameshifting happens at a slippery heptamer with the zero frame sequence, X-XXY-YYZ (where X could be any nucleotide, Y is a weakly base-pairing nucleotide and Z is species specific). Upon reaching this sequence, the tRNAs in the P and A sites of the ribosome (reading XXY and YYZ respectively) simultaneously slip to the −1 frame (XXX-YYY). In the new frame, at least two base-pairs are preserved between each of the two tRNAs and the mRNA. (In a few cases, the base-pairing in the new frame is stronger than the pairing in the original frame). The most important feature of this sequence is its repetitive nature. In fact, the sequence AAA-AAA-G is the shiftiest in E. coli and can support as much as 2% −1 frameshifting.17,35 Mutations that disrupt the runs of XXX or YYY severely decrease frameshifting. Strong base-pairing in the YYY sequence, for example by introducing runs of three C-s or G-s, can also lead to reduced frameshifting.5,36

A refinement of the simultaneous slippage model proposed by Weiss et al postulated that the slip occurs after peptidyl transfer (explaining why the “A-site” tRNA inserts its amino acid in the final polypeptide product) but before, or more likely during, ribosomal translocation.35 Presumably, when the ribosome is in this state and when base-pairing between the A-site tRNAs and the message is weak, some kind of inherent special stereochemical configuration in the decoding site of the ribosome allows the A- and P-site tRNAs to simultaneously slip back by one nucleotide relative to the mRNA. Favorable base-pairing in the new position “locks” the ribosome in the new frame.

Cis-Acting mRNA Sequences Stimulate Simultaneous Slippage

Several cis-acting sequences are known to stimulate frameshifting at slippery heptamers. The most common is an RNA secondary structure downstream of the shift site. In almost all cases in eukaryotes, this downstream structure is an RNA pseudoknot, on average six nucleotides 3' of the heptamer.37 Although in individual cases the distance between the pseudoknot and shift site is optimized (i.e., it varies from one example to another), changing it by as little as two nucleotides in either direction reduces or completely eliminates the stimulatory effect.36 A number of different types of RNA pseudoknots are known to stimulate simultaneous slip events.37 Instead, in a few cases, mostly in prokaryotes, the frameshift is stimulated by a stem-loop structure; either a simple stem-loop or in some cases a more complex branching structure.38 In one case, the 3' stimulator is more than 3,800 nucleotides downstream of the frameshift site.39 One model is that all of these RNA structures stimulate the frameshift event by stalling the ribosome at the shift site, thus allowing more time for the recoding event to take place. However, their function is not as simple as this. Some RNA structures, both pseudoknots and stem-loops, are perfectly good ribosome “stallers” but cannot stimulate frameshifting.4042

In several prokaryotic cases, slippery −1 frameshift events are enhanced by 5' stimulators. Such stimulators have been described in a number of insertion sequences and in the chromosomal dnaX gene. In all known cases, the stimulator is a Shine-Dalgarno (SD) type sequence that acts by pairing with its complementary sequence near the 3' end of 16S rRNA of translating ribosomes. The optimal distance between the shift site and the SD sequence is between 9 and 14 nucleotides. Exact spacing is not as critical as the position of the downstream stimulators, but bringing the sequences closer, 2 to 4 nucleotides, leads to inhibition of frameshifting. One explanation for the SD-like stimulator is that it may help “pull” the ribosome backwards to facilitate the −1 frameshift. The spacing requirement for optimal stimulatory effect is consistent with this explanation. In addition, the SD-like interaction may help “stall” the ribosome at the recoding site long enough for the recoding event to occur.

P-Site Events

“P-site” mechanisms can be invoked to explain a large number of recoding events including +1 and −1 frameshifting, and ribosomal hopping. What all of these events and stop codon readthrough have in common is that they occur when the P site is occupied by a peptidyl-tRNA and the adjacent A site is unoccupied. The vacant A site provides a slowdown in standard decoding, facilitating the recoding event to take place. Simplest to describe is the mechanism of translational readthrough.

By the time the first examples of programmed translational readthrough became known, studies of nonsense suppression had “paved the way” by showing competition at stop codons between termination and chain propagation. Nonsense suppressors are mutants that allow the translation of mRNAs containing premature, in-frame nonsense codons. Such mutants, broadly, fall into two categories. Most nonsense suppressors are mutations in tRNAs that alter the anticodon loop so that the mutant tRNA can base-pair with a termination codon.4346 The base-pairing tRNA inserts an amino acid in place of one of the three stop codons, thus extending translation past the internal nonsense codon. Most non-tRNA suppressors are mutations in the genes encoding release factor proteins, prfA4749 and prfB50,51 in E. coli , SUP35 and SUP45 in S. cerevisiae.52 These mutations lead to reduced translational termination efficiency. By hampering termination, they allow effective competition of a near-match tRNA for the corresponding nonsense codons, thus stimulating the nonstandard decoding event.

Cis-Acting Sequences Stimulate Stop Codon Readthrough

At sites of programmed readthrough, cis-acting mRNA signals partially “disable” termination of translation. The well-known cis-acting stimulators of readthrough are located downstream of the recoding site. Certain sequences immediately 3' of a termination codon are preferred for efficient termination.53 This phenomenon known as “3' context” is exploited by some programmed readthrough site for achieving optimum efficiency of recoding.54 Such sites have evolved 3' contexts that are suboptimal for termination.

A 3' pseudoknot is very important for stop codon readthrough of the gag gene terminator of Murine Leukemia Virus (MLV) and a minority of other retroviruses.37,55 The naturally occurring pseudoknot in MLV cannot be substituted with the pseudoknot that stimulates frameshift in Mouse Mammary Tumor Virus (MMTV).55 The special features of the readthrough stimulatory pseudoknot presumably mean that causing a pause is not the main feature of the pseudoknot and interference with termination may be critically important. Another 3' readthrough stimulator of uncertain nature is present in Barley Dwarf Yellow Virus PAV coat protein gene. Amazingly, in this case the stimulatory element is situated nearly 700 bases 3' of the readthrough stop codon.56

+1 Frameshifting

Most of the small number of known cases of recoding in chromosomal genes involve +1 frameshifting events, which can be explained by a P-site mechanism. This includes the genes prfB (encoding RF2) in E. coli, EST3 and ABP140 in S. cerevisiae, and antizyme in metazoans. Initial data came from analysis of the frameshifting event in decoding prfB. As discussed above, the analysis showed that frameshifting occurs on the last sense codon of a short ORF1 at the sequence CUU-U. The last U of this sequence is part of the in-frame stop codon UGA. Frameshifting occurs when the peptidyl tRNA slips from CUU to UUU in the +1 frame. The stability of base-pairing in the new position is crucial.23 A pause at the 0 frame A-site is also crucial as the levels of release factor can directly modulate frameshifting efficiency. High levels of RF2, which increase the efficiency of termination and thus reduce pausing at the UGA stop codon, lead to reduced levels of frameshifting. The reverse is also true.

The frameshift event occurring during translation of yeast Ty1 Gag-Pol mRNA provides an important variation in the P-site theme,57 which was also revealed in studies of the consequence of amino acid starvation.5860 With Ty1, a +1 frameshift event occurs on the sequence CUU-AGG-C. The tRNA decoding CUU is in the P site and the A site of the ribosome is empty. Again, the peptidyl tRNA slips in the +1 direction relative to the mRNA to form two base pairs with the codon UUA. Unlike prfB, the pause is provided by a “hungry” sense codon rather than a termination codon. The tRNA that decodes AGG in S. cerevisiae is rare, and the AGG codon itself is also rare. This leads to a slower rate of decoding while the P-site tRNA in the ribosome is primed for slippage. Consistent with this, overexpression of the tRNA recognizing AGG codons significantly reduces the frameshifting potential of the Ty1 frameshift site,57 while deleting this tRNA gene from the genome increases frameshifting on the Ty1 site even further.12

A different type of mechanism has been proposed for Ty3 frameshifting.7 In this case, +1 frameshifting occurs on the sequence GCG-AGU-U, and, again, the first codon (GCG) is in the P site and the A-site AGU codon is vacant. As with all P-site events, ribosomal pausing at the rare AGU codon is important; however, the mechanism of shifting frames has been interpreted differently. The cognate tRNA that decodes the GCG codon cannot form standard base-pairs with the +1 codon CGA and it was proposed that tRNA slippage is not involved. Instead, it was proposed that the P-site tRNA somehow interferes with normal decoding in the adjacent A site, which allows incoming tRNAs to contact the +1 GUU codon out-of-frame. Consistent with this hypothesis, overexpression of the tRNA for GUU increases the levels of frameshifting.61

However, several recent results cast doubt on the necessity for invoking two separate mechanisms to explain the known cases of +1 frameshifting. Initial analysis of the frameshift site of mammalian antizyme 1 revealed that the tRNA, which is in the P-site during recoding, could not form good base-pairing with the next available +1 codon (though substantially better than in Ty3 frameshifting). This was even more obvious with several P-site mutants, which could otherwise support efficient frameshifting. Therefore, a Ty3-like mechanism was proposed.27 However, when the same sequence was tested in S. cerevisiae for its frameshift potential, it supported a ribosomal shift to the +1 frame but mostly via −2 shifting (90% of the time) rather than the +1 shift (10% of the time) seen in mammals.62 This happens even though the UCC P-site codon is recognized by tRNAs that have the same anticodon in mammals and yeast. Something similar was observed when the antizyme frameshift cassette was tested in S. pombe.63 In S. pombe, 80% of the shift product result from a +1 shift and 20% result from a −2 shift. It is clear that the −2 shift can occur only as a result of re-pairing. It seems improbable that the same sequence can induce two rare and mechanistically different recoding events. More likely, the two antizyme mRNA decoding events are related through a single P-site re-pairing mechanism.

More recent experiments with the two yeast +1 frameshift sites, those of Ty1 and Ty3, suggest that in both cases the P-site codon:anticodon pairing is sub-standard.64 Consistent with this, overexpressing the genes for P-site tRNAs that gave standard pairing with the codons involved, dramatically reduced +1 frameshifting on both Ty1 and a Ty3-like recoding sites. Deleting the cognate P-site tRNAs for a modified Ty1 site significantly increased frameshifting. For Ty1, the explanation for these results is that unstable tRNA: mRNA contacts combined with ribosome stalling on “hungry” A-site codons leads to a slip of the tRNA relative to the mRNA. From their earlier experiments Farabaugh and colleagues reasonably proposed that the P-site tRNA at the Ty3 frameshift site does not dissociate but that the nature of the P-site codon:anticodon interaction influences the immediate 3' codon base so that it is unavailable for pairing with an incoming tRNA.7,64 Instead A-site bases 2,3 and 4 pair with an incoming tRNA so that the frame is shifted +1. Recent results have shown that, at least for bypassing, the requirements for successful “re-pairing” of mRNA to P-site tRNA in the shifted position may be surprisingly minimal (A. J. Herr, personal communication). While bypassing may differ from single nucleotide frameshifting in ribosome contacts with mRNA, it is tempting to consider that minimal “re-pairing” may suffice for programmed frameshifting of Ty3 also - if the shift tRNA presumed to be involved by Farabaugh and colleagues is the correct one.64 If so, then a single type of dissociation/re-pairing model may apply to both Ty1 and Ty3, and all other known cases of +1 frameshifting. For Ty3 frameshifting, it is not possible, by simple mutagenesis experiments, to distinguish between a model that involves “once-only pairing and occlusion of the first A-site codon base” and a re-pairing model. Currently both models seem viable.

Cis-Acting mRNA Sequences Stimulating +1 Frameshifting

Cis-acting stimulators of P-site frameshfting events are noted for their variety. A 5' stimulator of P-site recoding is an SD-like sequence just upstream of the frameshift site of prfB, the first example of a 5' stimulator in recoding.21 This sequence is placed only three nucleotides 5' of the CUU-U shift site (i.e., much closer than its location for stimulating −1 frameshifting in dnaX). The distance is crucial. Moving the SD sequence even by one base in either direction greatly reduces frameshifting. In this case, the close distance between the SD and the recoding site is thought to physically “push” the ribosome sitting on the frameshift site in the +1 direction.

Another 5' stimulator is a 40–50 nucleotides sequence placed upstream of the mammalian antizyme 1 and 2 genes, which stimulates frameshifting 2.5–5 fold.30,62 Little is known about its mechanism of action, but it appears to exert its activity through primary nucleotide sequence and not the peptide it encodes (S. Matsufuji, personal communication). Several potential interactions have been proposed between this stimulator and rRNAs (O. Matveeva, personal communication) but none of them have been tested. It is clear that this stimulator is modular. It appears to have evolved in three separate stages over 1 billion years, with the modules evolving in order of their proximity to the shift site.30 Antizyme genes have also evolved at least two 3' stimulators. The best studied case is an RNA pseudoknot several nucleotides downstream of the frameshift site.27 This pseudoknot exists in two related versions, one in the vertebrate orthologs of antizyme 1 and the other in the vertebrate orthologs of antizyme 2. As with pseudoknots in −1 simultaneous slippage, spacing to the recoding site is important. Furthermore, in S. cerevisiae, where the mammalian antizyme sequence supports mostly −2 frameshifting, moving the pseudoknot by three nucleotides downstream results in a dramatic increase of the proportion of ribosomes shifting in the +1 direction.62 This again demonstrates that RNA pseudoknots do more than just stall ribosomes on the recoding sites by performing additional function(s). The endogenous S. pombe antizyme 3' stimulator is not a recognizable pseudoknot and, though its nature is obscure, it is likely to be a new type of stimulatory element.65

Another interesting 3' stimulator is a short 7–15 nucleotide sequence immediately downstream of the frameshift site of Ty3 that stimulates frameshifting about 7.5 fold.7 This sequence is thought to interfere with A-site decoding by forming base-pairing with helix 18 of 18S rRNA.66 Finally, just like readthrough, P-site frameshifting events that are stimulated by an A-site stop codons have evolved 3' sequences that provide a poor 3' termination context. This is most obvious in a phylogenetic analysis of the known antizyme sequences. In every case where sufficient data is available, the 3' context of the antizyme gene in question is least favorable for termination.30 This is especially striking because different taxonomic groups have different 3' context requirements.

Ribosomal Hopping

Ribosomal hopping can be seen as an extreme case of translational frameshifting. Therefore, its mechanism can be viewed as a variation of P-site slippage resulting in +1 frameshifting. Most of our knowledge about ribosomal hopping comes from work on bacteriophage T4 gene 60, which encodes a subunit of phage topoisomerase.67,68 At the end of gene 60 ORF1, up to half of all translating ribosomes bypass 50 nucleotides and then resume normal translation on a second downstream ORF2.69 Three stages define this remarkable event. During the first stage (take-off ), the P-site tRNA dissociates from the P-site GGA codon. In the next stage (scanning), the ribosome traverses the coding gap checking for a matching P-site codon. In the last stage (landing), the P-site tRNA-mRNA pairing is re-established and regular translocation resumes. The original A-site codon is a (slowly decoded) UAG stop codon. For efficient landing, matching take-off and landing codons are essential. Several mutants that reduce gene 60 bypassing have been isolated and all of them map to the tRNA gene tRNA2Gly that decodes the P-site GGA codon.70 These mutant tRNAs seem perfectly capable of dissociating from the P-site codon but are unable to find the landing site.71,72

Cis-Acting mRNA Sequences Stimulate Ribosome Hopping

Several cis-acting elements stimulate the ribosomal hopping in gene 60. One is a downstream stem/loop structure that partially overlaps the take-off site.68 It appears that this structure interferes with normal decoding of the in-frame A-site termination codon.71 How it does this is not clear. When the wild type structure is substituted with a more stable counterpart, the efficiency of recoding drops indicating that it is not just the energy of melting the structure that is important. The sequence GAG 5' of the landing site may function as an SD-like element but this has not yet been established (C. Rettberg and F. Adamski, personal communication). The length of the coding gap also seems to effect the efficiency of bypassing but the reason for that is not clear.72 Finally, an unusual 5' stimulator element exists in gene 60. Interestingly, this stimulator works through the nascent peptide it encodes rather than its primary nucleotide sequence.68 The most important property of this nascent peptide is its positive charge provided by several arginines.73 It appears that the role of this element is to induce dissociation between the P-site tRNA and the mRNA.71,74

Selenocysteine Incorporation

A remarkable and unique example of codon redefinition is the encoding of selenocysteine. Selenocysteine is a 21st amino acid that is incorporated directly into polypeptide chains during translation in a number of bacteria, archaea and eukaryotes. The majority of studied selenoproteins are enzymes involved in oxidation-reduction reactions and contain selenocysteine in the active site. Selenocysteine is encoded by a UGA codon, which commonly specifies termination. In all three taxa, translation of UGA as selenocysteine requires distinct signals in the mRNA (termed SECIS elements for Selenocysteine Insertion Sequence), a unique tRNA that has a UCA anticodon and is charged with selenocysteine, an elongation factor which is specific for this tRNA and several enzymes essential for Sec-tRNASec biogenesis (for recent reviews, see refs. 7578 and references therein and Ch. 4 by Blanquet et al).

The mechanism has been extensively studied in E. coli and it appears to be similar in a number of other bacteria (Fig. 4A). The UGA codon specifying selenocysteine is followed by a stem/loop structure in the selenoprotein mRNA.79 Aside from a few conserved nucleotides in the apical loop and in the bulge of the stem-loop, only the secondary structure is important (Fig. 5A).80 The conserved nucleotides are responsible for interaction with the special elongation factor, SelB, which in turn binds Sec-tRNASec. SelB is a homologue of elongation factor Tu,81 which delivers all other tRNAs to the ribosome, but not the Sec-tRNASec.82 Unlike EF-Tu, SelB has a C-terminal extension domain,83 which binds the stem-loop structure in the mRNA. The binding of the SelB in complex with Sec-tRNASec and GTP to the RNA hairpin places the complex in the vicinity of the A-site of the ribosome and facilitates incorporation of selenocysteine into polypeptide chain.84

Figure 4. Models for selenocysteine incorporation into proteins.

Figure 4

Models for selenocysteine incorporation into proteins. A) in bacteria; B) in archaea ; C) eukaryotes.

Figure 5. Secondary structure of Selenocysteine Insertion Sequences.

Figure 5

Secondary structure of Selenocysteine Insertion Sequences. Conserved nucleotides are in bold. A) bacterial; B) archaeal; C) and D) eukaryotic SECIS elements. Form II differs from Form I by the presence of an additional small hairpin on top of the conserved (more...)

Archaeal and animal mechanisms (Fig. 4B,C) of selenocysteine incorporation are more complex. Although the SECIS elements have different secondary structures and conserved elements between archaea and eukaryotes (Fig. 5B-D), they do share a common feature. Unlike in E. coli, these SECIS elements are located in the 3' UTRs.8587

How the SECIS element in the 3'UTR dictates UGAs, sometimes kilobases upstream, to specify selenocysteine has been a major question for the past decade. The last couple of years has been fruitful in this regard and yet has raised even more questions. The long-sought elongation factor homologue EFSec was finally identified in the archaeon Methanococcus jannaschii88 and subsequently throughout the animal kingdom from C. elegans to humans.89,90 Just like its bacterial counterpart, EFSec binds Sec-tRNASec, has a GTP binding domain and possesses GTPase activity. Nevertheless, it is unable to bind the SECIS element.

Several proteins that bind SECIS element have been reported.91,92 However, only one of them, SBP2, identified in rats, binds specifically to the wild-type SECIS RNA,93 coprecipitates with EFSec from cotransfected cells and stimulates selenocysteine incorporation in rabbit reticulocyte lysates and transfected cells. Gel-filtration experiments show that SBP2 is a part of a large supramolecular complex. Consequently, it was proposed that SBP2 binds to SECIS elements in the 3'UTRs and recruits other components of the selenocysteine insertion machinery to translating or initiating ribosomes. The nature of these components, aside form EFSec and the tRNA, remains a mystery.

Eukaryotic SECIS elements are long stem-loop structures, which have certain important conserved features.94 First are the sequences (A/G)UGA and GA in the 5' and 3' sides respectively of the SECIS stem (Fig. 5C,D). It was proposed that these sequences form a quartet of non-Watson-Crick base pairs, with G-A, A-G tandem pairs in the center.95 Another conserved feature in SECIS is a stretch of two or three adenosines in the apical loop or bulge. The distance from the A-G, G-A tandem sequence to the stretch of adenosines is fixed at 9–11 base pairs, which is approximately one helical turn of A-form RNA.

Recently, analysis of ribosomal RNA structure revealed a number of G-A, A-G base pairs similar to the ones observed in SECIS elements. They play a key role in formation of a common RNA structure, which is termed a kink-turn, or K-turn, that interacts with a number of proteins with L7Ae RNA-binding motif.96 SBP2 has the same motif, and mutations in it abrogate binding to the SECIS element and/or function in selenocysteine insertion.97 Therefore, it is possible that interactions of SBP2 with SECIS are similar to interactions between a number of ribosomal proteins and kink-turn motifs in rRNA.

Another intriguing question is whether translation of selenoprotein mRNAs is efficient and whether or not it is processive. The efficiency of reading a single UGA as selenocysteine has been measured at about 3–7%,98 and introduction of second UGA was reported to drop it to a marginal level.99 However, selenoprotein P (SelP) mRNA contains 10 UGA codons in humans and rats,100,101 12 in cattle and 17 in zebrafish,102,103 and all of them seem to be translated as selenocysteines in vivo. If the selenocysteine incorporation at each UGA is inefficient, then mRNAs with multiple UGAs, like SelP, are unlikely to be synthesized at detectable level. Therefore, either incorporation can be efficient at certain UGAs, or ribosomes translating selenoprotein's mRNA are somehow modified at translation initiation to read UGA as selenocysteine instead of ceasing translation. Nevertheless, the ability of such putatively modified ribosomes to insert selenocysteine is likely to depend on the context of the UGA since multiple isoforms of selenoprotein P have been found and these result from termination at some UGAs.101

The sequences surrounding UGA codon are extremely important for efficient insertion of selenocysteine. It has been shown that the identity of the two 5' codons, as well as of the 3' base dramatically influences the ratio between selenocysteine incorporation and termination.54,104,105 It is possible that some other yet unknown elements in the mRNA affect selenocysteine incorporation. While these elements are tuned in endogenous mRNA to achieve maximum reading, they could be absent in experimental constructs. In accord with this, Tujebajeva et al did succeed in expressing full-length recombinant selenoprotein P.106 But it should be noted that the expression was achieved only in one of the three cell lines tried. Therefore, it is possible that experiments in transfected cells do not always reflect the correct situation in vivo and their success can depend on a number of variables.

Early attempts to express selenoproteins in vitro failed. Recently, expression was achieved in a rabbit reticulocyte lysate with a single modification of the standard procedure: a 10-fold decrease of mRNA levels.93 It is likely that, under limited conditions, different components necessary for selenoprotein mRNA translation are distributed between different mRNAs and form unproductive complexes. A similar situation could occur in transfection experiments when cells are overloaded with selenoprotein mRNA. In fact, it was observed that the ratio of termination product to full-length selenoprotein increases when the amounts of transfected DNA increase.107 Supplementation of selenium, co-introduction of selenocysteine tRNA and sometimes SelD, stimulates incorporation several fold in transfected cells. Interestingly, while supplementation of SBP2 enhances expression of iodothyronine deiodinase 1, phospholipid glutathione peroxidase and thioredoxin reductase (all containing one selenocysteine codon) a few fold, supplementation increases expression of SelP up to 22 fold! Moreover, SBP2 doesn't readily exchange between SECIS elements.108 Thus, during transfection experiments, SBP2 is probably predominantly bound to endogenous mRNAs, with the majority of transfected mRNAs being left unbound.

The nonsense-mediated decay (NMD) pathway can serve as a key regulator of the amounts of endogenous selenoprotein mRNA and establish stoichiometry between the levels of selenoprotein mRNA and ligands necessary for selenocysteine insertion. The NMD pathway serves to degrade mRNA containing premature termination codons, which otherwise could produce detrimental truncated proteins. A stop codon is recognized as premature if it is located more than 50–55 nucleotides upstream from the 3'-most exon-exon junction.109 Under limited selenium, the UGA codon of selenoprotein glutathione peroxidase 1 is recognized as nonsense and triggers mRNA degradation.110,111 This suggests that if other components of the selenocysteine insertion pathway are limited, selenocysteine codons might be recognized as premature stop codons and mRNAs would be degraded, provided that the spacing between UGA and last exon-exon junction is met. Remarkably, in most selenoprotein genes the selenocysteine-encoding UGA is located in mRNA so that it can be recognized as premature and trigger mRNA degradation if translation is terminated at it. On the contrary, cDNA based expression constructs used in transfection experiments lack exon-exon junctions, and therefore produce mRNAs that are not subject to NMD, even if translation is terminated at UGA. SBP2 has different affinities for different SECIS elements.108 It is proposed that SBP2 establishes an expression hierarchy between mRNAs of different selenoproteins, which becomes crucial under limitation of selenium. The other function of SBP2 could be the preselection of ribosomes for selenoprotein translation as, in the absence of mRNA, it was found to be tightly associated with ribosomes.97 It could also be that binding of SBP2 alters the competence of the ribosome for termination and/or NMD.

Conclusion—Overview of the Field

A small but steady stream of new recoding examples is discovered each year. The majority are found in the compact genomes of viruses and transposable elements. Nevertheless, a growing number are being discovered in chromosomal genes. It is clear that only a minority of chromosomal genes employ recoding for their expression. However, recoding events are difficult to find and undoubtedly only a fraction of them is known. Currently, recoding events are discovered when the synthesis of a protein product with a known biochemical activity cannot be explained by standard decoding. An example is the recently described +1/−2 frameshifting in a hepatitis C virus gene.112 A polypeptide shorter than that resulting from standard decoding was discovered. Initially, this polypeptide was dismissed as a product of posttranslational processing but the researchers tested for potential frameshifting. While this particular example needs further study, it does highlight that potential cases of recoding are easy to overlook. This presents a significant limitation for the rate of discovery of novel recoding examples. It has long been known that protein synthesis of a single mRNA leads to the production of a number of products (appearing as faint bands on SDS gels), sometimes bigger, sometimes shorter, than the main product. It is usually assumed that these result from preferential ribosome drop-off or from posttranslational modifications (degradation, phosphorylation, etc.). It is conceivable that at least a fraction of these products are the result of recoding events. In most cases a minor product is never investigated if it constitutes less than 10% of the main product. Our knowledge from viral recoding events shows that frameshifting/readthrough at as little as 1–2% can be physiologically significant. It is therefore possible that a large number of recoding events are currently hidden from us by limitations in technology or by our biased assumptions.

The years of incremental research has made our understanding of recoding more detailed to the point where the first attempts at general searching have been made. This approach is still in its early stages and no new recoding examples have been discovered with its application. Computer modeling using empirical data is another approach in the attempt to discover new cases of recoding. This latter approach is less comprehensive (and more biased) but promises more immediate results. Several candidate genes are being currently investigated as a result (I.P. Ivanov, unpublished). The availability of whole genome sequences greatly improves the opportunities. Database searches utilizing unique features of selenocysteine insertion machinery proved to be successful. Developed programs allow scanning of entire genomes for the presence of SECIS elements and analyze their position relative to predicted ORF-s. Candidate genes can be submitted to experimental verification. This approach has helped in discovering several mammalian113,114 and Drosophila115,116 selenoproteins and in identifying selenoproteins in zebrafish.102 Remarkably, mutations in one such in silico identified novel selenoprotein, selenoprotein N, were just shown to cause muscular dystrophy in humans.117

Recent advances in proteomics, especially combining peptide detection with sophisticated computational algorithms, that allow assignment of individual peptide to a particular ORF, offer great promise for recoding research. This technique has the advantage of being least biased, since it does not rely on knowledge of previously identified recoding sites. The technical challenges, however, are great.

The final and potentially greatest hope comes for the recent discoveries in the structure and function of the ribosome. It is difficult to overstate the significance of these developments and likely future understanding of the conformational changes that take place during protein synthesis. Extension to recoding will throw light on the role of stimulatory elements and how events at the recoding sites exemplify the richness of decoding.


We greatly appreciate the comments of Pavel V. Baranov. We are supported by NIH (grants GM61200 to R.FG. and GM 48152 to J.F.A.) and DOE grant DE-FG03-01ER63132 to R.F.G.


Gesteland RF, Atkins JF. Recoding: Dynamic reprogramming of translation. Annu Rev Biochem. 1996;65:741–768. [PubMed: 8811194]
Brierley I. Ribosomal frameshifting viral RNAs. Gen Virol. 1995;76:1885–1892. [PubMed: 7636469]
Farabaugh PJ. Programmed translational frameshifting. Annu Rev Genet. 1996;30:507–528. [PubMed: 8982463]
Jacks T, Townsley K, Varmus HE. et al. Two efficient ribosomal frameshifting events are required for synthesis of mouse mammary tumor virus gag-related polyproteins. Proc Natl Acad Sci USA. 1987;84:4298–4302. [PMC free article: PMC305072] [PubMed: 3035577]
Dinamn JD, Icho T, Wickner RB. A −1 ribosomal frameshift in a double-stranded RNA virus of yeast forms a gag-pol fusion protein. Proc Natl Acad Sci USA. 1991;88:174–178. [PMC free article: PMC50772] [PubMed: 1986362]
Tzeng T-H, Tu C-L, Bruenn JA. Ribosomal frameshifting requires a pseudoknot in the Saccharomyces cerevisiae double-stranded RNA virus. J Virol. 1992;66:999–1006. [PMC free article: PMC240802] [PubMed: 1731118]
Farabaugh PJ, Zhao H, Vimaladithan A. A novel programed frameshift expresses the POL3 gene of retrotransposon Ty3 of yeast: frameshifting without tRNAslippage. Cell. 1993;74:93–103. [PubMed: 8267715]
Parkin NT, Chamorro M, Varmus HE. Human immunodeficiency virus type 1 gag-pol frameshifting is dependent on downstream mRNA secondary structure: Demonstration by expression in vivo. J Virol. 1992;66:5147–5151. [PMC free article: PMC241392] [PubMed: 1321294]
Bidou L, Stahl G, Grima B. et al. In vivo HIV-1 frameshifting efficiency is directly related to the stability of the stem-loop stimulatory signal. RNA. 1997;3:1153–1158. [PMC free article: PMC1369557] [PubMed: 9326490]
Dinman JD, Wickner RB. Ribosomal frameshifting efficiency and gag/gag-pol ratio are critical for yeast M1 double-stranded RNA virus propagation. J Virol. 1992;66:3669–3676. [PMC free article: PMC241150] [PubMed: 1583726]
Shehu-Xhilaga M, Crowe SM, Mak J. Maintenance of the Gag/Gag-Pol ratio is important for human immunodeficiency virus type 1 RNA dimerization and viral infectivity. J Virol. 2001;75:1834–1841. [PMC free article: PMC114093] [PubMed: 11160682]
Kawakami K, Pande S, Faiola B. et al. A rare tRNA-Arg(CCU) that regulates Ty1 element ribosomal frameshifting is essential for Ty1 retrotransposition in Saccharomyces cerevisiae. Genetics. 1993;135:309–320. [PMC free article: PMC1205637] [PubMed: 8243996]
Tsuchihashi Z, Kornberg A. Translational frameshifting generates the γ subunit of DNA polymerase III holoenzyme. Proc Natl Acad Sci USA. 1990;87:2516–2520. [PMC free article: PMC53720] [PubMed: 2181440]
Blinkowa AL, Walker JR. Programmed ribosomal frameshifting generates the Escherichia coli DNA polymerase III γ subunit from within the τ subunit reading frame. Nucleic Acids Res. 1990;18:1725–1729. [PMC free article: PMC330589] [PubMed: 2186364]
Flower AM, McHenry CS. The γ subunit of DNA polymerase III holoenzyme of Escherichia coli is produced by ribosomal frameshifting. Proc Natl Acad Sci USA. 1990;87:3713–3717. [PMC free article: PMC53973] [PubMed: 2187190]
Larsen B, Wills NM, Gesteland RF. et al. rRNA-mRNA base pairing stimulates a programmed −1 ribosomal frameshift. J Bacteriol. 1994;176:6842–6851. [PMC free article: PMC197052] [PubMed: 7961443]
Larsen B, Gesteland RF, Atkins JF. Structural probing and mutagenic analysis of the stem-loop required for E. coli dnaX ribosomal frameshifting: programmed efficiency of 50% J Mol Biol. 1997;271:47–60. [PubMed: 9300054]
Gao D, McHenry CS. τ binds and organizes Escherichia coli replication proteins through distinct domains. J Biol Chem. 2001;276:4433–4440. [PubMed: 11078743]
Craigen WJ, Caskey CT. Expression of peptide chain release factor 2 requires high-efficiency frameshift. Nature. 1986;322:273–275. [PubMed: 3736654]
Weiss RB, Dunn DM, Atkins JF. et al. 1987. Slippery runs, shifty stops, backward steps, and forward hops: −2, −1, +1, +2, +5, and +6 ribosomal frameshifting. Cold Spring Harb Symp Quant Biol. 1987;52:687–693. [PubMed: 3135981]
Weiss RB, Dunn DM, Dahlberg AE. et al. Reading frame switch caused by base-pair formation between the 3' end of 16S rRNA and the mRNA during elongation of protein synthesis in Escherichia coli. EMBO J. 1988;7:1503–1507. [PMC free article: PMC458402] [PubMed: 2457498]
Curran JF, Yarus M. Use of tRNA suppressors to probe regulation of Escherichia coli release factor 2. J Mol Biol. 1988;203:75–83. [PubMed: 3054124]
Curran JF. Analysis of effects of tRNA:message stability on frameshift frequency at the Escherichia coli RF2 programmed frameshift site. Nucleic Acids Res. 1993;21:1837–1843. [PMC free article: PMC309422] [PubMed: 8493101]
Major LL, Poole ES, Dalphin ME. et al. Is the in-frame termination signal of the Escherichia coli release factor-2 frameshift site weakened by a particularly poor context? Nucleic Acids Res. 1996;24:2673–2678. [PMC free article: PMC145990] [PubMed: 8758994]
Atkins JF, Lewis JB, Anderson CW. et al. Enhanced differential synthesis of proteins in a mammalian cell-free system by addition of polyamines. J Biol Chem. 1975;250:5688–95. [PubMed: 167021]
Miyazaki Y, Matsufuji S, Hayashi S. Cloning and characterization of a rat gene encoding ornithine decarboxylase antizyme. Gene. 1992;113:191–197. [PubMed: 1572540]
Matsufuji S, Matsufuji T, Miyazaki Y. et al. 1995. Autoregulatory frameshifting in decoding mammalian ornithine decarboxylase antizyme. Cell. 1995;80:51–60. [PubMed: 7813017]
Rom E, Kahana C. Polyamines regulate the expression of ornithine decarboxylase antizyme in vitro by inducing ribosomal frameshifting. Proc Natl Acad Sci USA. 1994;91:3959–3963. [PMC free article: PMC43702] [PubMed: 8171019]
Howard MT, Shirts BH, Zhou J. et al. Cell culture analysis of the regulatory frameshift event required for the expression of mammalian antizyme. Genes to Cells. 2001;6:331–341. [PubMed: 11733031]
Ivanov IP, Gesteland RF, Atkins JF. Antizyme expression: a subversion of triplet decoding, which is remarkably conserved by evolution, is a sensor for an autoregulatory circuit. Nucleic Acids Res. 2000;17:3185–3196. [PMC free article: PMC110703] [PubMed: 10954585]
Kurland CG. Reading-frame errors on ribosomesIn: Celis JE, Smith JD, eds.Nonsense Mutations and tRNA Suppressors New York: Academic,197997–108.
Kurland CG. Translational accuracy and the fitness of bacteria. Annu Rev Genet. 1992;26:29–50. [PubMed: 1482115]
Baranov PV, Gurvich OL, Fayet O. et al. RECODE: a database of frameshifting, bypassing and codon redefinition utilized for gene expression. Nucleic Acids Res. 2001;29:264–267. [PMC free article: PMC29850] [PubMed: 11125107]
Jacks T, Madhani HD, Masiarz FR. et al. Signals for ribosomal frameshifting in the Rous sarcoma virus gag-pol region. Cell. 1988;55:447–458. [PubMed: 2846182]
Weiss RB, Dunn DM, Shuh M. et al. E. coli ribosomes re-phase on retroviral frameshift signals at rates ranging from 2 to 50 percent. New Biol. 1989;1:159–169. [PubMed: 2562219]
Brierley I, Jenner AJ, Inglis SC. Mutational analysis of the “slippery-sequence” component of a coronavirus ribosomal frameshifting signal. J Mol Biol. 1992;227:463–479. [PubMed: 1404364]
ten Dam EB, Pleij CW, Bosch L. RNA pseudoknots: translational frameshifting and readthrough on viral RNAs. Virus Genes. 1990;4:121–136. [PubMed: 2402881]
Rettberg CC, Prere MF, Gesteland RF. et al. A three-way junction and constituent stem-loops as the stimulator for programmed −1 frameshifting in bacterial insertion sequence IS911. J Mol Biol. 1999;286:1365–1378. [PubMed: 10064703]
Paul CP, Barry JK, Dinesh-Kumar SP. et al. A sequence required for −1 ribosomal frameshifting located four kilobases downstream of the frameshift site. J Mol Biol. 2001;310:987–999. [PubMed: 11502008]
Somogyi P, Jenner AJ, Brierley I. et al. Ribosomal pausing during translation of an RNA pseudoknot. Mol Cell Biol. 1993;13:6931–6940. [PMC free article: PMC364755] [PubMed: 8413285]
Somogyi P, Jenner AJ, Brierley I. et al. Ribosomal pausing during translation of an RNA pseudoknot. Mol Cell Biol. 1993;13:6931–6940. [PMC free article: PMC364755] [PubMed: 8413285]
Lopinski JD, Dinman JD, Bruenn JA. Kinetics of ribosomal pausing during programmed −1 translational frameshifting. Mol Cell Biol. 2000;20:1095–1103. [PMC free article: PMC85227] [PubMed: 10648594]
Eggertsson G, Soll D. Transfer ribonucleic acid-mediated suppression of termination codons in Escherichia coli. Microbiol Rev. 1988;52:354–374. [PMC free article: PMC373150] [PubMed: 3054467]
Kohli J, Kwong T, Altruda F. et al. Characterization of a UGA-suppressing serine tRNA from Schizosaccharomyces pombe with the help of a new in vitro system for eukaryotic suppressor tRNAs. J Biol Chem. 1979;254:1546–1551. [PubMed: 762155]
Kondo K, Hodgkin J, Waterston RH. Differential expression of five tRNA(UAGTrp) amber suppressors in Caenorhabditis elegans. Mol Cell Biol. 1988;8:3627–35. [PMC free article: PMC365418] [PubMed: 3221861]
Hatfield DL, Smith DW, Lee BJ. et al. Structure and function of suppressor tRNAs in higher eukaryotes. Crit Rev Biochem Mol Biol. 1990;25:71–96. [PubMed: 2183969]
Oeschger MP, Oeschger NS, Wiprud et al. High efficiency temperature-sensitive amber suppressor strains of Escherichia coli K12: isolation of strains with suppressor-enhancing mutations. Mol Gen Genet. 1980;177:545–52. [PubMed: 6991863]
Ryden SM, Isaksson LA. A temperature-sensitive mutant of Escherichia coli that shows enhanced misreading of UAG/A and increased efficiency for some tRNA nonsense suppressors. Mol Gen Genet. 1984;193:38–45. [PubMed: 6419024]
Zhang S, Ryden-Aulin M, Isaksson LA. Functional interaction between tRNAGly2 at the ribosomal P-site and RF1 during termination at UAG. J Mol Biol. 1998;284:1243–1246. [PubMed: 9878344]
Kawakami K, Inada T, Nakamura Y. Conditionally lethal and recessive UGA-suppressor mutations in the prfB gene encoding peptide chain release factor 2 of Escherichia coli. J Bacteriol. 1988;170:5378–81. [PMC free article: PMC211618] [PubMed: 3053663]
Karow ML, Rogers EJ, Lovett PS. et al. Suppression of TGA mutations in the Bacillus subtilis spoIIR gene by prfB mutations. J Bacteriol. 1998;180:4166–4170. [PMC free article: PMC107413] [PubMed: 9696765]
Stansfield I, Tuite MF. Polypeptide chain termination in Saccharomyces cerevisiae. Curr Genet. 1994;25:385–95. [PubMed: 8082183]
Poole ES, Major LL, Mannering SA. et al. Translational termination in Escherichia coli: three bases following the stop codon crosslink to release factor 2 and affect the decoding efficiency of UGA-containing signals. Nucl Acids Res. 1998;26:954–960. [PMC free article: PMC147352] [PubMed: 9461453]
McCaughan KK, Brown CM, Dalphin ME. et al. Translational termination efficiency in mammals is influenced by the base following the stop codon. Proc Natl Acad Sci USA. 1995;92:5431–5435. [PMC free article: PMC41708] [PubMed: 7777525]
Wills NM, Gesteland RF, Atkins JF. Pseudoknot-dependent read-through of retroviral gag termination codons: importance of sequences in the spacer and loop2. EMBO J. 1994;13:4137–4144. [PMC free article: PMC395336] [PubMed: 8076609]
Brown CM, Dinesh-Kumar SP, Miller WA. Local and distant sequences are required for efficient readthrough of the barley yellow dwarf virus PAV coat protein gene stop codon. J Virol. 1996;70:5884–5892. [PMC free article: PMC190606] [PubMed: 8709208]
Belcourt MF, Farabaugh PJ. Ribosomal frameshifting in the yeast retrotransposon Ty: tRNAs induce slippage on a 7 nucleotide minimal site. Cell. 1990;62:339–352. [PubMed: 2164889]
Weiss R, Gallant J. Mechanism of ribosome frameshifting during translation of the genetic code. Nature. 1983;302:389–393. [PubMed: 6339944]
Lindsley D, Gallant J. On the directional specificity of ribosome frameshifting at a “hungry” codon. Proc Natl Acad Sci USA. 1993;90:5469–5473. [PMC free article: PMC46742] [PubMed: 8516288]
Gallant J, Lindsley D, Masucci J. The unbearable lightness of peptidyl-tRNA In: Garrett R, Douthwaite SR, Liljas A et al. eds.The Ribosome Washington, DC: ASM Press,2000385–396.
Pande S, Vimaladithan A, Zhao H. et al. Pulling the ribosome out of frame by +1 at a programmed frameshift site by cognate binding of aminoacyl-tRNA. Mol Cell Biol. 1995;15:298–304. [PMC free article: PMC231956] [PubMed: 7799937]
Matsufuji S, Matsufuji T, Wills NM. et al. Reading two bases twice: mammalian antizyme frameshifting in yeast. EMBO J. 1996;15:1360–1370. [PMC free article: PMC450040] [PubMed: 8635469]
Ivanov IP, Gesteland RF, Matsufuji S. et al. Programmed frameshifting in the synthesis of mammalian antizyme is +1 in mammals, predominantly +1 in fission yeast, but −2 in budding yeast. RNA. 1998;4:1230–1238. [PMC free article: PMC1369695] [PubMed: 9769097]
Sundararajan A, Michaud WA, Qian Q. et al. Near-cognate peptidyl-tRNAs promote +1 programmed translational frameshifting in yeast. Mol Cell. 1999;4:1005–1015. [PubMed: 10635325]
Ivanov IP, Matsufuji S, Murakami Y. et al. Conservation of polyamine regulation by translational frameshifting from yeast to mammals. EMBO J. 2000;19:1907–1917. [PMC free article: PMC302018] [PubMed: 10775274]
Li Z, Stahl G, Farabaugh PJ. Programmed +1 frameshifting stimulated by complementarity between a downstream mRNA sequence and an error-correcting region of rRNA. RNA. 2001;7:275–284. [PMC free article: PMC1370085] [PubMed: 11233984]
Huang WM, Ao SZ, Casjens S. et al. A persistent untranslated sequence within bacteriophage T4 DNA topoisomerase gene 60. Science. 1988;239:1005–1012. [PubMed: 2830666]
Weiss RB, Huang WM, Dunn DM. A nascent peptide is required for ribosomal bypass of the coding gap in bacteriophage T4 gene 60. Cell. 1990;62:117–26. [PubMed: 2163764]
Maldonado R, Herr AJ. Efficiency of T4 gene 60 translational bypassing. J Bacteriol. 1998;180:1822–1830. [PMC free article: PMC107096] [PubMed: 9537381]
Herr AJ, Atkins JF, Gesteland RF. Mutations which alter the elbow region of tRNA2Gly reduce T4 gene 60 translational bypassing efficiency. EMBO J. 1999;18:2886–2896. [PMC free article: PMC1171369] [PubMed: 10329634]
Herr AJ, Gesteland RF, Atkins JF. One protein from two open reading frames: mechanism of a 50 nt translational bypass. EMBO J. 2000;19:2671–2680. [PMC free article: PMC212773] [PubMed: 10835364]
Herr AJ, Wills NM, Nelson CC. et al. Drop-off during ribosome hopping. J Mol Biol. 2001;311:445–452. [PubMed: 11492998]
Larsen B, Peden J, Matsufuji S. et al. Upstream stimulators for recoding. Biochem Cell Biol. 1995;73:1123–1129. [PubMed: 8722029]
Herr AJ, Nelson CC, Wills NM. et al. Analysis of the roles of tRNA structure, ribosomal protein L9, and the bacteriophage T4 gene 60 bypassing signals during ribosome slippage on mRNA. J Mol Biol. 2001;309:1029–1048. [PubMed: 11399077]
Berry MJ. Recoding UGA as Selenocysteine In: Sonenberg N, Hershey JWB, Mathews MB, eds.Translational Control of Gene Expression Cold Spring Harbor: Cold Spring Harbor Laboratory Press,2000763–783.
Kohrl J, Brigelius-Flohe R, Bock A. Selenium in biology: facts and medical perspectives. Biol Chem. 2000;381:849–864. [PubMed: 11076017]
Huttenhofer A, Bock A. RNA structures involved in selenoprotein synthesis In: Simons R, Grunberg-Manago M, eds.RNA structure and FunctionCold Spring Harbor: Cold Spring Harbor Laboratory Press,1998603–639.
Atkins JF, Bock A, Matsufuji S. et al. Dynamics of the genetic code In: Gesteland RF, Cech TR, Atkins JF, eds.The RNA World 2nd ed. Cold Spring Harbor: Cold Spring Harbor Laboratory Press,1999637–673.
Zinoni F, Heider J, Bock A. Features of the formate dehydrogenase mRNA necessary for decoding of the UGA codon as selenocysteine. Proc Natl Acad Sci USA. 1990;87:4660–4664. [PMC free article: PMC54176] [PubMed: 2141170]
Heider J, Baron C, Bock A. Coding from a distance: dissection of the mRNA determinants required for the incorporation of selenocysteine into protein. EMBO J. 1992;11:3759–3766. [PMC free article: PMC556836] [PubMed: 1396569]
Forchhammer K, Leinfelder W, Bock A. Identification of a novel translation factor necessary for the incorporation of selenocysteine into protein. Nature. 1989;342:453–456. [PubMed: 2531290]
Forster C, Ott G, Forchhammer K. et al. Interaction of a selenocysteine-incorporating tRNA with elongation factor Tu from E. coli. Nucleic Acids Res. 1990;18:487–491. [PMC free article: PMC333452] [PubMed: 2408012]
Kromayer M, Wilting R, Tormay P. et al. Domain structure of the prokaryotic selenocysteine-specific elongation factor SelB. J Mol Biol. 1996;262:413–420. [PubMed: 8893853]
Ringquist S, Schneider D, Gibson T. et al. Recognition of the mRNA selenocysteine insertion sequence by the specialized translational elongation factor SELB. Genes Dev. 1994;8:376–385. [PubMed: 8314089]
Berry MJ, Banu L, Chen YY. et al. Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3' untranslated region. Nature. 1991;353:273–276. [PubMed: 1832744]
Wilting R, Schorling S, Persson BC. et al. Selenoprotein synthesis in archaea: identification of an mRNA element of Methanococcus jannaschii probably directing selenocysteine insertion. J Mol Biol. 1997;266:637–641. [PubMed: 9102456]
Rother M, Resch A, Gardner WL. et al. Heterologous expression of archaeal selenoprotein genes directed by the SECIS element located in the 3' non-translated region. Mol Microbiol. 2001;40:900–908. [PubMed: 11401697]
Rother M, Wilting R, Commans S. et al. Identification and characterisation of the selenocysteine- specific translation factor SelB from the archaeon Methanococcus jannaschii. J Mol Biol. 2000;299:351–358. [PubMed: 10860743]
Tujebajeva RM, Copeland PR, Xu XM. et al. Decoding apparatus for eukaryotic selenocysteine insertion. EMBO Rep. 2000;1:158–163. [PMC free article: PMC1084265] [PubMed: 11265756]
Fagegaltier D, Hubert N, Yamada K. et al. Characterization of mSelB, a novel mammalian elongation factor for selenoprotein translation. EMBO J. 2000;19:4796–805. [PMC free article: PMC302067] [PubMed: 10970870]
Hubert N, Walczak R, Carbon P. et al. A protein binds the selenocysteine insertion element in the 3'-UTR of mammalian selenoprotein mRNAs. Nucleic Acids Res. 1996;24:464–469. [PMC free article: PMC145655] [PubMed: 8602359]
Fujiwara T, Busch K, Gross HJ. et al. A SECIS binding protein (SBP) is distinct from selenocysteyl-tRNA protecting factor (SePF) Biochimie. 1999;81:213–218. [PubMed: 10385002]
Copeland PR, Fletcher JE, Carlson BA. et al. A novel RNA binding protein, SBP2, is required for the translation of mammalian selenoprotein mRNAs. EMBO J. 2000;19:306–314. [PMC free article: PMC305564] [PubMed: 10637234]
Berry MJ, Banu L, Harney JW. et al. Functional characterization of the eukaryotic SECIS elements which direct selenocysteine insertion at UGA codons. EMBO J. 1993;12:3315–3322. [PMC free article: PMC413599] [PubMed: 8344267]
Walczak R, Westhof E, Carbon P. et al. A novel RNA structural motif in the selenocysteine insertion element of eukaryotic selenoprotein mRNAs. RNA. 1996;2:367–379. [PMC free article: PMC1369379] [PubMed: 8634917]
Klein DJ, Schmeing TM, Moore PB. et al. The kink-turn: a new RNA secondary structure motif. EMBO J. 2001;20:4214–4221. [PMC free article: PMC149158] [PubMed: 11483524]
Copeland PR, Stepanik VA, Driscoll DM. Insight into mammalian selenocysteine insertion: domain structure and ribosome binding properties of Sec insertion sequence binding protein 2. Mol Cell Biol. 2001;21:1491–1498. [PMC free article: PMC86695] [PubMed: 11238886]
Berry MJ, Maia AL, Kieffer JD. et al. Substitution of cysteine for selenocysteine in type I iodothyronine deiodinase reduces the catalytic efficiency of the protein but enhances its translation. Endocrinology. 1992;131:1848–52. [PubMed: 1396330]
Nasim MT, Jaenecke S, Belduz A. et al. Eukaryotic selenocysteine incorporation follows a nonprocessive mechanism that competes with translational termination. J Biol Chem. 2000;275:14846–14852. [PubMed: 10809727]
Hill KE, Lloyd RS, Yang JG. et al. The cDNA for rat selenoprotein P contains 10 TGA codons in the open reading frame. J Biol Chem. 1991;266:10050–3. [PubMed: 2037562]
Himeno S, Chittum HS, Burk RF. Isoforms of selenoprotein P in rat plasma. Evidence for a full-length form and another form that terminates at the second UGA in the open reading frame. J Biol Chem. 1996;271:15769–75. [PubMed: 8663023]
Kryukov GV, Gladyshev VN. Selenium metabolism in zebrafish: multiplicity of selenoprotein genes and expression of a protein containing 17 selenocysteine residues. Genes Cells. 2000;5:1049–1060. [PubMed: 11168591]
Tujebajeva RM, Ransom DG, Harney JW. et al. Expression and characterization of nonmammalian selenoprotein P in the zebrafish, Danio rerio. Genes Cells. 2000;5:897–903. [PubMed: 11122377]
Liu Z, Reches M, Engelberg-Kulka H. A sequence in the Escherichia coli fdhF “selenocysteine insertion sequence” (SECIS) operates in the absence of selenium. J Mol Biol. 1999;294:1073–1086. [PubMed: 10600367]
Grundner-Culemann E, Martin GW 3rd, Tujebajeva R. et al. Interplay between termination and translation machinery in eukaryotic selenoprotein synthesis. J Mol Biol. 2001;310:699–707. [PubMed: 11453681]
Tujebajeva RM, Harney JW, Berry MJ. Selenoprotein P expression, purification, and immunochemical characterization. J Biol Chem. 2000;275:6288–6294. [PubMed: 10692426]
Berry MJ, Harney JW, Ohama T. Selenocysteine insertion or termination: factors affecting UGA codon fate and complementary anticodon:codon mutations. Nucleic Acids Res. 1994;22:3753–9. [PMC free article: PMC308358] [PubMed: 7937088]
Low SC, Grundner-Culemann E, Harney JW. et al. SECIS-SBP2 interactions dictate selenocysteine incorporation efficiency and selenoprotein hierarchy. EMBO J. 2000;19:6882–6890. [PMC free article: PMC305907] [PubMed: 11118223]
Zhang J, Sun X, Qian Y. et al. Intron function in the nonsense-mediated decay of beta-globin mRNA: indications that pre-mRNA splicing in the nucleus can influence mRNA translation in the cytoplasm. RNA. 1998;4:801–815. [PMC free article: PMC1369660] [PubMed: 9671053]
Moriarty PM, Reddy CC, Maquat LE. Selenium deficiency reduces the abundance of mRNA for Se-dependent glutathione peroxidase 1 by a UGA-dependent mechanism likely to be nonsense codon-mediated decay of cytoplasmic mRNA. Mol Cell Biol. 1998;18:2932–2939. [PMC free article: PMC110672] [PubMed: 9566912]
Weiss SL, Sunde RA. Cis-acting elements are required for selenium regulation of glutathione peroxidase-1 mRNA levels. RNA. 1998;4:816–827. [PMC free article: PMC1369661] [PubMed: 9671054]
Xu Z, Choi J, Yen TS. et al. Synthesis of a novel hepatitis C virus protein by ribosomal frameshift. EMBO J. 2001;20:3840–3848. [PMC free article: PMC125543] [PubMed: 11447125]
Lescure A, Gautheret D, Carbon P. et al. Novel selenoproteins identified in silico and in vivo by using a conserved RNA structural motif. J Biol Chem. 1999;274:38147–38154. [PubMed: 10608886]
Kryukov GV, Kryukov VM, Gladyshev VN. New mammalian selenocysteine-containing proteins identified with an algorithm that searches for selenocysteine insertion sequence elements. J Biol Chem. 1999;274:33888–33897. [PubMed: 10567350]
Martin-Romero FJ, Kryukov GV, Lobanov AV. et al. Selenium metabolism in Drosophila: selenoproteins, selenoprotein mRNA expression, fertility, and mortality. J Biol Chem. 2001;276:29798–804. [PubMed: 11389138]
Castellano S, Morozova N, Morey M. et al. In silico identification of novel selenoproteins in the Drosophila melanogaster genome. EMBO Rep. 2001;2:697–702. [PMC free article: PMC1083988] [PubMed: 11493597]
Moghadaszadeh B, Petit N, Jaillard C. et al. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet. 2001;29:17–18. [PubMed: 11528383]
Copyright © 2000-2013, Landes Bioscience.
Bookshelf ID: NBK6406


  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...