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1.
FIG. 1

FIG. 1. From: Posttranscriptional Control of Gene Expression in Yeast.

Scheme outlining the pathway of eukaryotic transcripts from the nucleus to the sites of translation and decay in the cytoplasm. This review focuses primarily on the posttranscriptional steps of gene expression after nuclear transport. Reproduced from reference 364 with permission of the publisher.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
2.
FIG. 12

FIG. 12. From: Posttranscriptional Control of Gene Expression in Yeast.

The model of CPA1 regulation by arginine, originally proposed by Werner et al. (588). The key feature of this proposal is that the peptide product of the uORF is involved in blocking the passage of ribosomes beyond the end of the uORF in the presence of arginine. The induced pausing of the ribosome may involve a regulatory protein called CPAR, but no details are currently known.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
3.
FIG. 16

FIG. 16. From: Posttranscriptional Control of Gene Expression in Yeast.

Features of yeast mRNAs influencing stability. The major types of mRNA stability determinant reported so far for S. cerevisiae are shown. The majority of these elements act to destabilize the mRNAs in which they have been studied. Internal stop codons (here indicated as UAA) can cause strong destabilization in 5′-proximal positions (strong) but have less or no effect at more distal positions (weak). Apart from the cap or poly(A) tail, it is not clear whether discrete (and transferable) stabilizing elements exist.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
4.
FIG. 14

FIG. 14. From: Posttranscriptional Control of Gene Expression in Yeast.

Different forms of frameshifting in S. cerevisiae. Two types of +1 frameshifting have been described. (A) The first type, observed in the yeast transposable element Ty1, involves re-pairing from the CUU codon to the +1 UUA codon. (B) The second type, described for Ty3, does not seem to involve re-pairing by the decoding tRNA interacting with the first codon of the “slippage site.” (C) Finally, the retroviral type of −1 frameshifting occurs in the dsRNA viruses of S. cerevisiae.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
5.
FIG. 18

FIG. 18. From: Posttranscriptional Control of Gene Expression in Yeast.

Polysome disruption as a key process in mRNA degradation. An integrated scheme of mRNA decay events in yeast is shown. Triggering events are generally likely to disrupt the mRNP and polysome structure, which may therefore constitute the common intermediate step leading to further decay events. Since mRNA interacts with both nuclear and cytoplasmic proteins on its pathway through the nucleus into the cytoplasm, the interactions with both groups of proteins may be relevant to the control of mRNA degradation. Further research is expected to reveal whether this mechanism or more specific coupling mechanisms underlie decay pathways.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
6.
FIG. 17

FIG. 17. From: Posttranscriptional Control of Gene Expression in Yeast.

A major route of mRNA decay in yeast. Specific elements in the body of the mRNA are proposed to dictate (possibly via interactions with Pab1p) the rate of deadenylation by a PAN-type enzyme (complex). Once a shortened tail has been generated, the major pathway involves the triggering of decapping by Dcp1p (or Dcp2p), which is then followed by 5′→3′ exonucleolytic decay (catalyzed by Xrn1p). The Mrt proteins may modulate decapping. Alternatively, exonucleolytic degradation from the 3′ end has been observed. It is now suspected that the multienzyme “exosome,” or something like it, is involved in this process.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
7.
FIG. 15

FIG. 15. From: Posttranscriptional Control of Gene Expression in Yeast.

“Networked” interactions involving components of S. cerevisiae eIF4F. The diagram shows interactions defined in the following ways: physical interactions demonstrated biochemically in vitro (binding, +; competition or negative regulation, −) and genetic (functional) interactions that are synthetically lethal or potentiate a negative effect (−) or are of a positive, phenotype-suppressing nature (+). The various interactions are discussed in the text. These are not the only interactions detected for the respective proteins, but they suffice to illustrate the functional complexity of the yeast translation system. These and other results are consistent with the existence of multiple interactions, functional overlaps, and alternative routes to initiation in vivo. Translation, therefore, like many other cellular processes, is not definable in terms of an independent linear pathway involving dedicated components.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
8.
FIG. 5

FIG. 5. From: Posttranscriptional Control of Gene Expression in Yeast.

This scheme compares the overall structures and known or predicted binding sites of mammalian eIF4GI (242, 312, 346, 605), its two counterparts in S. cerevisiae (180), and wheat p86 (6, 373). The sites of cleavage by the proteases 2A and L and of the RNA-binding motifs (RNP) are also indicated. The potential eIF3 binding and RNA-binding motifs in yeast proteins have been deduced from sequence comparisons. There is no evidence for the existence of an eIF4A-binding site in the yeast eIF4Gs, whereas there are two such domains in mammalian eIF4G (242). The protein structures are approximately arranged in order to line up the homologous regions. Wheat p86 is thought to have a binding site for microtubules at the C terminus (58). There has been uncertainty about the N-terminal sequence of eIF4GI (181), which is now thought to include a Pabp-binding site (509a). Further examples of eIF4G or of eIF4G-like proteins are discussed in the text.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
9.
FIG. 9

FIG. 9. From: Posttranscriptional Control of Gene Expression in Yeast.

Pathways of translational initiation in prokaryotic and eukaryotic cells. These are formalized comparisons of the main options available to prokaryotic and eukaryotic ribosomes encountering mRNA molecules. 5′-end or cap-dependent initiation is typical of eukaryotic mRNAs, but there is only an apparent counterpart process on certain prokaryotic mRNAs (pathway 1). Internal initiation, by contrast, is common on prokaryotic mRNAs (pathway 2) but is efficient only on the small percentage of eukaryotic mRNAs that possess an IRES. Finally, initiation can be coupled to a previous termination event on the same mRNA (pathway 3). Reinitiation is apparently complex in both prokaryotic and eukaryotic systems. Both prokaryotic and eukaryotic ribosomes can be involved in reinitiation. However, the stability of binding, the effective off-rates, and the (re)start site selection process differ significantly. Moreover, de novo internal initiation on a prokaryotic mRNA can also be tied in to termination on the upstream ORF via a “facilitated-binding” mechanism (see the text). Many details of eukaryotic reinitiation are unknown.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
10.
FIG. 6

FIG. 6. From: Posttranscriptional Control of Gene Expression in Yeast.

Conserved sequence and structural motifs in eIF4E. Comparison of eIF4E sequences from a range of different organisms reveals the presence of many strictly conserved or conservatively maintained features (boldface type). A number of these are involved in binding the mRNA cap structure (arrows), while others are surface residues (dots), some of which have the potential to be involved in interactions with other proteins (such as eIF4G, 4E-BPs, or p20) (354, 358, 449). Asterisks mark the positions of serine residues in the respective eIF4E sequences that have either been shown or are suspected to be sites of phosphorylation. The sequences shown belong to eIF4E proteins that bind preferentially to the m7GpppX type of mRNA cap. Caenorhabditis elegans has multiple forms of the cap-binding protein (not shown here), at least two of which also recognize m32,2,7GpppX caps (269a). Relatively few differences in the primary sequences apparently suffice to confer this broader specificity on the C. elegans cap-binding proteins.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
11.
FIG. 7

FIG. 7. From: Posttranscriptional Control of Gene Expression in Yeast.

Amino acids involved in binding to eIF4G and p20 map to a predicted surface-accessible cluster on the dorsal surface of S. cerevisiae eIF4E (449). Based on the crystal structure of the mouse (Δ27) eIF4E protein (354) and the NMR structure of yeast eIF4E (358), these groups of residues are predicted to lie together on the opposite face of yeast eIF4E from the cap-binding slot. They belong to α-helices 1 and 2, respectively, or are associated with a β-strand (β1) that follows the variable N-terminal region of the eIF4E sequence. The ribbon model shown here is based on the coordinates of the published NMR structure (358). The view is of the dorsal face angled to show the site clearly. The structure of the N-terminal region of the protein is unclear and has been cut off at the top of this representation. The amino acids that affect the binding of the eIF4E-binding domains of eIF4G and of p20 (V71 and W75) are dark grey. The other amino acids seem to influence only binding to the eIF4E-binding domain of eIF4G (E72, H37, P38, L39, and G139).

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
12.
FIG. 13

FIG. 13. From: Posttranscriptional Control of Gene Expression in Yeast.

The S. cerevisiae mRNAs YAP1 and YAP2 have different types of uORF, which affect translation and mRNA stability in distinct ways. (A) Elimination of the respective uORFs via mutation of the start codons (AUG→AAG; crosses in the construct maps) reveals striking differences which are most readily detected by using a reporter gene (in this case LUC, encoding luciferase. Removal of the uORF from the natural YAP1 leader (puY1) has little effect on translation or mRNA stability (pΔuY1). The YAP2 uORFs, in contrast, have been found to influence translation and mRNA stability (here reflected in changed steady-state mRNA levels). Both translation and relative mRNA levels were increased upon removing either YAP2 uORF1 (pΔu1Y2) or YAP2 uORF2 (pΔu2Y2) or both uORFs [pΔu(1+2)Y2] from the 5′UTR. The wild-type and mutant sequences of the YAP1 uORF and YAP2 uORF1 are indicated. (B) Mechanism by which the YAP2 uORFs affect mRNA decay. The Northern blots show the disappearance of the YAP2 mRNA signal as a consequence of inactivating the PolII promoter in a heat-sensitive rpb1 mutant. The destabilization effect is largely UPF1 independent. Reproduced from reference 572 with permission of the publisher.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
13.
FIG. 3

FIG. 3. From: Posttranscriptional Control of Gene Expression in Yeast.

Rate control exercised at different steps of translation. (A) The general scheme indicates the flow rates (j values, in events per unit time for binding and release and in nucleotides per unit time for elongation) assigned to the respective steps of 40S ribosomal subunit binding (jB), 60S junction (jI), elongation (jE), and 40S/60S release (jT). For the purpose of illustrating certain general points, the release rates for 40S and 60S are assumed here to be identical, although this is unlikely to apply to at least some mRNAs. (B) At a low relative rate of elongation (jE1), ribosome packing on the mRNA is high. (C) A reduced packing density occurs at a higher elongation rate (jE2). However, variation in jE need not have a strong effect on overall ribosomal throughput on a given mRNA if the jB and jI rates are not too high. (D) On the other hand, if termination and initiation are coupled, jT may exercise an important control function on translation as a whole.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
14.
FIG. 4

FIG. 4. From: Posttranscriptional Control of Gene Expression in Yeast.

Steps of translational initiation in S. cerevisiae. The recycling of eIF-GDP and the suspected dynamics of eIF4F complex formation are indicated schematically. p20 competes with eIF4G for binding to eIF4E, but the means by which this competitive interaction is regulated has yet to be determined. It is now thought to be primarily eIF4F that binds the cap (see next section). The interaction of Pab1p with eIF4G may provide an alternative route to mRNA-ribosome joining, but the significance of such a process in vivo is unknown. In yeast, the relationship between eIF4A-eIF4B helicase/annealing activity and scanning is still controversial. By analogy to mammalian models, other initiation factors have been included in the 43S preinitiation complex that is thought to perform scanning. Many questions remain the subject of further investigation, such as what happens to eIF4F during each cycle of initiation (see Fig. 8) and how eIF3 promotes initiation. It is not known whether scanning is strictly unidirectional. The release of most of the eIFs and the joining of the ribosomal 60S subunit lead to polypeptide initiation. The recent reports on eIF4H (458) and yIF2 (89b), which are not included in this figure, emphasize that we do not yet know the full complement of factors involved in initiation.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
15.
FIG. 8

FIG. 8. From: Posttranscriptional Control of Gene Expression in Yeast.

Heterotropic cooperativity in eIF4E and the translational initiation cycle. A recent study has suggested testable models that can explain how p20 regulation (A) and cyclical eIF4F function (B) might be achieved (449). Binding of eIF4G to eIF4E induces a high-affinity cap-binding state in eIF4E (A). This promotes 40S-mRNA interactions and ultimately translational initiation. p20 can bind to part of the eIF4G-binding site on eIF4E (Fig. 7), potentially generating a dead-end complex unable to participate in the eIF4G-mediated initiation pathway. Since p20 binds with a lower affinity to eIF4E, it does not block translation but, rather, exerts fine regulation via competition with eIF4G for a shared site on eIF4E. Measurements of the relative binding affinities between these proteins (449) have provided the basis for understanding how a cyclical cap-eIF4E-binding pathway might function (B). The binding of eIF4G mediates both enhanced cap binding and association of the 40S ribosomal subunit. The relatively high affinity of eIF4G binding to eIF4E ensures that the latter binds to the 5′ cap almost exclusively as part of the eIF4F complex. Subsequently, and perhaps during scanning or as a result of 60S junction, a rearrangement of the preinitiation complex induces dissociation of eIF4E from eIF4G, which results in the loss of the high-affinity cap-binding state in eIF4E. As a result, eIF4E can be released relatively easily from the mRNA, thus becoming free to rebind eIF4G and thus restart another cycle. Reproduced from reference 449 with permission of the publisher.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
16.
FIG. 10

FIG. 10. From: Posttranscriptional Control of Gene Expression in Yeast.

Principles of kinetic control affecting prokaryotic and eukaryotic initiation. (A) A prokaryotic 30S ribosomal subunit has direct access to the SD sequence of an mRNA with an unstructured TIR. (B) Inhibition via structure in the TIR can be adequately modelled by assuming a thermodynamic control mechanism in which the steady-state distribution of folded and unfolded TIR dictates the amount of mRNA accessible to ribosome binding. (C) In the eukaryotic case, 40S ribosomal subunit binding can occur unhindered on a leader bearing localized structure, but the structured region is thought then to inhibit the scanning process. The off-rate (k3) for ribosomal subunits in this situation is unknown. Disruption of the secondary structure can be driven by an apparently ATP-dependent process, allowing resumption of scanning through the structured region. (D) Random internal binding of 40S ribosomal subunits to mRNA seems possible but is most probably not favored kinetically, and there may be kinetic or mechanistic restrictions on the ability of the subunits to become tightly associated with the mRNA. Initiation factors will influence the type of interaction entered into (compare Fig. 4). (E and F) 5′-end-dependent (E) or IRES-directed (F) initiation results in a tight association between the 40S subunit and the mRNA (the clasp is closed around the mRNA). It is not known whether scanning is normally unidirectional (E and F).

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
17.
FIG. 2

FIG. 2. From: Posttranscriptional Control of Gene Expression in Yeast.

Features of yeast mRNAs involved in the translation pathway relevant to control. (A) The 5′UTR stretches from the cap to the AUG start codon (positions 1 to 3). (B) Structural features in the 5′UTR that can influence translational efficiency (and mRNA stability) include secondary structures such as stem-loops and poly(G) sequences and short uORFs. uORFs can have a number of important properties, depending on their structure and sequence environment. The main coding region (positions 3 to 5) can sometimes include an in-frame stop codon that either is avoided by frameshifting or, in aberrant mRNAs, leads to premature termination (and mRNA destabilization). The 3′UTR and poly(A) tail (positions 5 to 7) influence the behavior of posttermination ribosomes at the end of the transcript, and at least the poly(A) tail has been implicated in the control of initiation. All of the numbered sites in panel A can be involved in key events of translation or mRNA turnover or act as targets for control mechanisms. The schemes shown are composites of the features of yeast mRNAs that can be involved in posttranscriptional control. Individual mRNAs differ with respect to the combination of the respective sites present. Panel A reproduced from reference 364 with permission of the publisher.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.
18.

FIG. 11. From: Posttranscriptional Control of Gene Expression in Yeast.

Features of GCN4 regulation involving modulation of eIF2 activity and the roles of short uORFs (222–227). (A) Diagram indicating the lengths (in nucleotides) of the respective uORFs and noncoding regions of the GCN4 leader. Since uORF2 and uORF3 are not essential for regulation, the scheme focuses on the roles of uORF1 and uORF4. The effects of alterations in the intercistronic distances on the estimated level of reinitiation on uORF4 and the measured rate of translation of GCN4 (as a GCN4::lacZ fusion) are indicated in columns above the illustration of the GCN4 leader. Also shown is a sketch representing simple theoretical gradients of reinitiation competence as a function of time and/or nucleotide sequence travelled in the repressed and derepressed states. These gradients have been used as the basis for a model of regulation of GCN4 repression mediated by changes in the status of eIF2 phosphorylation. It is, however, still uncertain how accurately they reflect the true dynamics of change in the status of ribosomal subunits on the GCN4 leader. These will undoubtedly be a complex function of both distance and various sequence effects. (B) Proposed cycle of events regulating the level of activity of eIF2 in the yeast cell. Under starvation conditions, part of the eIF2-GDP population is “sidelined” into a form restricting GDP-GTP exchange via phosphorylation of eIF2 by GCN2 kinase in response to increased levels of uncharged tRNA. See the text for further details and references.

John E. G. McCarthy. Microbiol Mol Biol Rev. 1998 December;62(4):1492-1553.

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