Department of Molecular and Cell Biology, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK1
Author for correspondence: Ian Stansfield. Tel: +44 1224 273106. Fax: +44 1224 273144. e-mail: i.stansfield{at}abdn.ac.uk
Keywords: translation termination, protein synthesis, stop codon, release factor, nonsense suppression
a These authors contributed equally to the work.
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Overview |
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The translation termination apparatus in eukaryotes and prokaryotes |
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The role of GTPase release factors in termination |
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In mouse, two eRF3 variants have been identified which differ in their N-terminal domain sequences and expression patterns in this organism (Hoshino et al., 1998 ). However, whether or not they have distinct activities in termination remains to be addressed. Intriguingly, one mouse eRF3 is known to interact with the C terminus of mammalian poly(A)-binding protein PABP (Hoshino et al., 1999
), raising a number of questions about the breadth of potential functions this protein may carry out, including involvement in the regulation of mRNA stability and, potentially, recycling post-termination ribosomes back to the 5' end of the mRNA to participate in new rounds of translation initiation (Hoshino et al., 1999
).
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RF recognition of the stop codon |
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Release factors and the reassignment of stop codons to sense |
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Amongst eukaryote micro-organisms, the ciliate species of the genera Paramecium and Tetrahymena use UAA and UAG to encode glutamine (Caron & Meyer, 1985 ), while Euplotes species signal stop using UAA and UAG only, with UGA encoding cysteine (Meyer et al., 1991
). Recently, an unclassified diplomonad species from the Hexamitidae has been discovered with an apparent stop codon reassignment to glutamine (Keeling & Doolittle, 1997
). These discoveries have led to the search for the corresponding tRNAs which decode the stop codons as sense. In Tetrahymena, a
and a
(where Um represents 2'-O-methyluridine) have anticodons cognate for UAG and UAA, respectively (Hanyu et al., 1986
; Kuchino et al., 1985
; Table 1
). A third
decodes both the glutamine codons CAA and CAG. The diplomonads with reassigned stop codons use similar
and
(Keeling & Doolittle, 1997
).
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The termination signal: stop codons and the role of flanking nucleotides |
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The 5' nucleotide context of a stop codon also influences how efficiently a stop codon directs termination. In E. coli, this operates partly through the identity of the penultimate amino acid residue in the nascent peptide, which influences termination efficiency by up to 30-fold (Mottagui-Tabar et al., 1994 ). Efficient termination events are associated with penultimate amino acid residues that are basic in nature. The nature of the C-terminal (ultimate) amino acid residue, whose codon is located immediately 5' to the termination signal, also modulates termination efficiency in E. coli (Bjornsson et al., 1996
). Termination efficiency is stimulated synergistically by pairings of the last two (ultimate and penultimate) amino acids of a polypeptide chain, which increase the propensity of
-helix or ß-sheet formation, pairings which are represented most frequently in highly expressed genes in both E. coli and Bacillus subtilis (Bjornsson et al., 1996
; Mottagui-Tabar & Isaksson, 1998
). The 5' codon context effect in E. coli is also partly mediated by the identity of the tRNA isoacceptor in the ribosomal P-site (Bjornsson et al., 1996
). In Saccharomyces cerevisiae, termination by eRF1 is less influenced by the penultimate amino acid in the peptide chain; the greater effect is exerted by the P-site tRNAs. While a P-site CAG-decoding glutamine tRNA is not particularly antagonistic to release factor binding, CAA-decoding
, when in the P-site, increases suppression of an A-site stop codon far more (Mottagui-Tabar et al., 1998
). These effects almost certainly occur through stearic interactions between the P-site tRNA and the release factor (Bjornsson et al., 1996
). Context effects thus have profound influences on termination efficiency in both prokaryotic and eukaryotic systems, and stop codon contexts which are poor substrates for eRF1 recognition are employed by viruses to direct stop codon suppression, as will be discussed below.
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Programmed stop codon readthrough |
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Viral and retrotransposon stop codon suppression
Translation of tobacco mosaic virus (TMV) main genomic RNA results in the synthesis of two polypeptides of 126 kDa and 183 kDa with a molar ratio of 20:1. Synthesis of the larger polypeptide results from the translational readthrough of a UAG stop codon, possibly by a which has known in vitro suppression activity (Pelham, 1978
; Beier et al., 1984
). This readthrough process is essential for viability of the virus and controls the level of RNA replicase (Ishikawa et al., 1986
). The five nucleotides following the stop codon with the consensus sequence UAG CAR YYA, including the cytosine nucleotide immediately 3' to the UAG stop codon, play an important role in readthrough of the TMV stop coding signal, stimulating 25% suppression (Skuzeski & Atkins, 1990
; Goelet et al., 1982
; Skuzeski et al., 1991
; Table 2
). Since no RNA secondary structural elements have been identified in the leaky stop codon environment (Goelet et al., 1982
), it seems likely that the 3' stop codon context alone directs readthrough (Skuzeski et al., 1991
). Programmed readthrough of the Qß bacteriophage coat protein gene UGA codon by a tRNATrp is also driven by nucleotide context 3' of the stop codon (Weiner & Weber, 1973
; Engelberg-Kulka, 1981
; Table 2
).
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Not all stop codon readthrough signals are solely dependent on primary sequence; some also have an RNA structural component (see Fig. 3). Moloney murine leukaemia virus (Mo-MuLV) is a well-studied example of a mammalian type C retrovirus that uses UAG stop codon readthrough, with glutamine insertion at the stop codon position to express the gag and gagpol fusion proteins in the 5% ratio required for virion production (Yoshinaka et al., 1985
). Cis-acting factors directing nonsense suppression include the sequence downstream of the stop codon, which has the ability to form an RNA pseudoknot structure with a minimal sequence requirement of 60 nt (Wills et al., 1991
; Feng et al., 1992
). While RNA pseudoknots are common cis signals which promote programmed ribosomal frameshifting in viral genomes (Brierley et al., 1989
), they cannot be regarded as generic RNA secondary structures which can trigger any recoding event; the mouse mammary tumour virus (MMTV) pseudoknot, found downstream of the MMTV frameshift site, while similar to the Mo-MuLV pseudoknot, is unable to functionally substitute for the Mo-MuLV structure (Gesteland & Atkins, 1996
).
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The mechanism by which an RNA pseudoknot can trigger stop codon readthrough or ribosomal frameshifting is unknown. Evidence from initiation-synchronized in vitro translation reactions suggests that pseudoknots pause ribosomes at the infectious bronchitis virus (IBV) frameshift site, although not all RNA secondary structures which cause pausing are sufficient to trigger frameshifting (Somogyi et al., 1993 ). During programmed stop codon readthrough, however, pseudoknots must perform a different overall function to that in stop codon readthrough, although there may still be a role for pseudoknots in pausing the ribosome. Clearly, by definition, readthrough of a stop codon implies a tRNA-mediated translation elongation event at the expense of release factor recognition of the stop codon. Interaction of the pseudoknot with the ribosome may favour tRNA interaction over eRF1 binding at the A-site, perhaps by distorting the mRNA structure, or constraining its flexibility. This might in turn restrict the necessary presentation of a stop codon to the release factor for recognition. Such presentation effects could operate synergistically with the unfavourable nucleotide context of the viral stop codon being read through to reduce the efficiency of eRF1-stop codon recognition.
Programmed stop codon readthrough in cellular genes
CFA/II strains of enterotoxigenic E. coli (ETEC) express three types of surface-associated hair-like fimbriae (coli surface antigens) known as CS1, CS2 and CS3. Expression of the genes required for biosynthesis and assembly of CS3 pili requires the suppression of an amber stop codon to produce a 104 kDa protein (Jalajakumari et al., 1989 ). While CFA/II strains have a nonsense suppressor mutant tRNAGln (supE), it is believed that in a wild-type tRNA background, the extended protein is still produced although its reduced abundance does not allow pilus synthesis (Jalajakumari et al., 1989
). The amino acid (glutamine) inserted by suppression at the stop codon is specifically required for protein activity, since when tyrosine is inserted by the supF tRNATyr, protein function is lost.
During translation in a range of species studied, UGA codons in cellular mRNAs can direct the insertion of a twenty-first amino acid, selenocysteine. This recoding event occurs in response to a specific set of trans factors and cis signals, which differ between eukaryotes and prokaryotes. Prokaryotes direct selenocysteine insertion at specific UGA codons using a 40 nt structured RNA sequence or SECIS element (Bock et al., 1991 ). The E. coli SelB protein, a homologue of the translation elongation factor EF-Tu, binds to the SECIS element using its C-terminal domain, bringing a UGA-decoding selenocysteine tRNASec to the UGA codon at the ribosomal A-site (Bock et al., 1991
; Kromayer et al., 1996
). In eukaryote systems, the SECIS element is located in the 3' untranslated region (UTR) of the mRNA encoding the selenoprotein, distal to the UGA codon directing selenocysteine incorporation, and the trans factors are less well characterized (Berry et al., 1993
, 1991
). Obviously, the key to selenocysteine UGA recoding is the elimination of release factor termination at the UGA selenocysteine signal. In eukaryote systems, this is in part achieved by the poor nucleotide context in which the selenocysteine UGA codons are found. Improving this context reduces selenocysteine incorporation at the expense of termination (McCaughan et al., 1995
). However, readthough efficiencies of 45% at the E. coli fdhF UGA selenocysteine codon and 75% at the mammalian deiodinase internal UGA codon indicate that recoding has variable efficiency (Suppmann et al., 1999
; McCaughan et al., 1995
). Apart from nucleotide context, the structured SECIS elements in both eukaryote and prokaryote systems are essential for UGA recoding. In prokaryotes, SECIS elements do not act simply to increase the local concentration of tRNASecSelB complex at the UGA codon, thus out-competing RF2; rather the SECIS element is required for delivery of the tRNASecSelBGTP ternary complex to the ribosome, and overexpressing the SelBtRNA combination does not increase the efficiency of incorporation (Suppmann et al., 1999
). This delivery mechanism, together with context effects, seems to be sufficient to much reduce alternative termination reactions. It seems likely the eukaryote SECIS elements function in the same way, although the mechanism used to achieve tRNASec UGA decoding when the SECIS element is located distally in the 3' UTR has not been established.
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Modulating termination efficiency using release factor concentration: eRF3 and [PSI] |
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eRF3 (Sup35p) in the [PSI+], aggregated state exists predominantly as cytoplasmic, high-molecular-mass oligomers, causing a weak nonsense suppressor phenotype. Release factor eRF1 (Paushkin et al., 1996 ) and Upf1p, a component of the mRNA surveillance complex which regulates nonsense-mediated decay, are both proteins which bind eRF3, and both are found incorporated into [PSI] eRF3 aggregates (Czaplinski et al., 1998
).
Inheritance of [PSI+] eRF3 occurs by cytoplasmic mixing, primarily through yeast mating, and results in the conversion of soluble eRF3 (Sup35p) into the aggregated [PSI+] form. The propagation of [PSI] is dependent upon proteinprotein interaction, and shows a spore (meiotic product) inheritance pattern of 4:0 [PSI+]:[psi-], characteristic of cytoplasmic, rather than nuclear, inheritance (Cox, 1965 ). The eRF3 [PSI+] prion exhibits many similarities to mammalian PrP prions, best illustrated by experiments to recreate de novo eRF3 (Sup35p) prion generation in vitro. Highly ordered amyloid-like fibres can be induced to form in vitro with purified eRF3, and fragments comprising the eRF3 N-terminal and middle domains (NM) or the N-terminal domain alone (Fig. 1
; Glover et al., 1997
). [PSI+]-form eRF3 fibres bind Congo red, are rich in ß-sheet and can adopt different conformations, which are maintained throughout the fibre once self-perpetuation is initiated (Glover et al., 1997
).
The eRF3 (Sup35p) protein is 685 amino acids in length and consists of three domains, each with different functions and properties (Fig. 1). The essential C-terminal domain of eRF3 is required for interaction with eRF1 in S. cerevisiae and Schizosaccharomyces pombe (Paushkin et al., 1997a
). A second eRF1-binding site may be present on eRF3 in S. cerevisiae, spanning the N-terminal domain and middle (M) domain of the release factor (Paushkin et al., 1997a
). As of yet, no designated function has been ascribed to the middle domain of eRF3.
The N-terminal domain, comprising the first 114 amino acid residues, contains four glutamine-rich degenerate nonapeptide repeats, and is not required for release factor activity (Teravanesyan et al., 1993 ). In spite of this, the domain has been conserved in all eukaryotic eRF3 proteins, although not all N-domains contain defined nonapeptide repeats. A number of lines of evidence indicate that the N-domain, with its peptide repeats, is centrally involved in [PSI] inheritance: (i) overexpression of eRF3 (Sup35p) fragments comprising either the N- and M-domains or N-terminal domain of eRF3 alone can induce a [PSI+] state de novo (Paushkin et al., 1997a
); (ii) single amino acid substitutions in one of the N-domain nonapeptide repeats results in mutant eRF3 (Sup35p) unable to propagate or support the [PSI+] state (Doel et al., 1994
; DePace et al., 1998
); (iii) increasing or decreasing the number of nonapeptide repeats in the eRF3 N-domain markedly increases or decreases, respectively, the spontaneous generation of the [PSI+] state in a [psi-] yeast (Liu & Lindquist, 1999
); and finally (iv) the fusion of SUP35 NM domains to GFP in a [PSI+] genetic background results in GFP aggregation in vivo (Patino et al., 1996
).
Environmental and genetic factors influence the loss and reacquisition of [PSI]
The ease with which aggregated [PSI+] eRF3 is inherited is mirrored by the efficiency with which a [PSI+] yeast strain can be converted to [psi-]. Known as curing, growth of a [PSI+] yeast in the presence of specific chemicals, such as guanidine hydrochloride (5 mM) or glycerol (2 M) can liberate soluble eRF3 (Sup35p) from pre-established [PSI+] aggregates, and hence produce an isogenic yeast which is [psi-] (Tuite et al., 1981 ). A [PSI+] state can be re-established by eRF3 overexpression (Chernoff et al., 1993
), although this phenomenon is strain dependent. Overexpression of the eRF3 NM domain is much more efficient at re-establishing a [PSI+] state (Paushkin et al., 1997b
).
Proteins that adopt aberrant conformations can be disaggregated in vivo by the activity of molecular chaperones (Parsell et al., 1994 ), and the activity of the heat-shock disaggregase protein Hsp104p can also play a role in the process of [PSI] curing, evidence that [PSI+] defines an altered aggregation state of eRF3 (Chernoff et al., 1995
; Schirmer & Lindquist, 1997
; Newnam et al., 1999
). Both overexpression and disruption of the HSP104 gene result in the loss of [PSI] (Chernoff et al., 1995
). Following Hsp104p overexpression, the [PSI+] state can be re-established by eRF3 (Sup35p) overexpression.
In addition to nonsense suppression itself, other discernible [PSI+] phenotypes, that of resistance to extreme temperatures and raised ethanol concentrations, have been detected (Eaglestone et al., 1999 ). Interestingly, the level of [PSI+]-mediated nonsense suppression was reduced when the [PSI+] strains were exposed to raised ethanol concentrations. Stress imposition thus produced transient reductions in the degree of eRF3 (Sup35p) aggregation in a [PSI+] strain, and thereby reduced nonsense suppression, without curing the [PSI+] state (Eaglestone et al., 1999
). The reduced suppression phenotype observed was reversible, and a [PSI+] state restored upon ethanol removal. Such reversible control of nonsense suppression frequencies may indicate that under certain stress conditions S. cerevisiae may use the [PSI+] state to control readthrough of a natural stop codon(s) with the consequent C-terminal extension of the polypeptide. However, no ORFs subject to [PSI]-programmed readthrough have yet been identified.
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tRNA suppressors of nonsense codons |
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Sense codon-cognate suppressor tRNAs
Ochre (UAA) mutations can be suppressed in yeast in vivo by increasing the copy number of a wild-type CAA-decoding (where U* represents modified uridine) (Pure et al., 1985
). A second yeast CAG-decoding
, can suppress amber UAG codons when expressed on a multi-copy plasmid (Weiss & Friedberg, 1986
). In both these cases, UAA and UAG suppression requires a first anticodon position G::U wobble base pairing (Table 2
). In another study, peptide sequencing identified amino acids inserted at the position of a premature UAG stop codon of a nonsense yeast STE6 allele. This stop codon, found in a nucleotide context unfavourable for eRF1 recognition, was suppressed by tyrosine, lysine and tryptophan tRNAs, although not by a tRNAGln as expected (Fearon et al., 1994
).
Many plant viruses, together with some animal viruses, rely for propagation on programmed stop codon readthrough events, generally of stop codons in nucleotide contexts unfavourable for eRF recognition. This ensures correct relative proportions of structural and enzymic virus translation products. This has stimulated the search for the naturally suppressing tRNAs responsible for the stop codon readthrough. In plants, a wheat cytoplasmic has been purified with in vitro UGA suppressor activity, a decoding event requiring a first codon position G:U wobble pairing (Baum & Beier, 1998
). A UGA stop codon in various virus programmed readthrough contexts was also efficiently suppressed in vitro by a plant
, involving a C:A mispairing at the third codon position (Urban et al., 1996
). A third plant tRNA, a
from tobacco, was also able to decode UGA in either the TMV or tobacco rattle virus (TRV) leaky contexts (Urban & Beier, 1995
). Finally, a plant
(where
represents pseudouridine) has been isolated that has both UAA and UAG suppression activity in vitro (Beier et al., 1984
). Decoding of UAA and UAG requires non-canonical G:A or G:G pairings at the third codon position, respectively.
In mammalian cells, the identity of natural suppressor tRNAs involved in programmed readthrough of the Mo-MuLV) has been inferred by identifying the amino acid inserted at the position corresponding to the suppressed stop codon. This revealed that both UAG and UAA can direct glutamine incorporation as well as termination events, while UGA directs arginine, cysteine and tryptophan insertion (Feng et al., 1990 ).
Clearly, similar isoacceptor tRNA species act as natural tRNA suppressors in different systems studied via first or third codon position wobble base pairing. In all cases, however, nonsense suppression frequency directed by these miscognate tRNAs is only detectable when the stop codon is placed in a nucleotide context unfavourable for eRF binding. Clearly the structural properties of the suppressor tRNAs themselves will contribute to their mis-decoding of stop codons, as well as their nucleoside modifications, which are known to affect nonsense suppression efficiency in yeast and other systems (Dihanich et al., 1987 ).
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Post-termination ribosomal fates |
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Ribosomes are released from the mRNA and recycled post-termination
Following termination, cells must recycle ribosomes, release factors and tRNAs to allow new rounds of protein synthesis. In prokaryotes, post-termination ribosome release requires the activity of the essential ribosome recycling factor (RRF; Janosi et al., 1998 ). A post-termination ribosomal complex becomes a pre-initiation complex via a two-step mechanism. Firstly, RRF and GTP-complexed EF-G together split the post-peptidyl-release ribosome into its component subunits. In the second step, the initiation factor IF3 acts to remove the deacylated tRNA from the ribosomal P-site (Freistroffer et al., 1997
; Pavlov et al., 1997
; Karimi et al., 1999
). In vivo, following termination and in the absence of RRF, prokaryote 70S ribosomes can remain on the mRNA and continue to slide downstream, and eventually reinitiate protein synthesis at any codon between 17 and 45 nt downstream in a frame-independent manner (Janosi et al., 1998
). In addition, RRF acting with EF-G can also reduce frameshift errors in vitro, and reduce missense translation error during peptide elongation (Janosi et al., 1996
), although the mechanism of this activity is not well understood. The recently solved crystal structure of RRF from Thermotoga maritima has revealed that this protein, like eRF1, is a tRNA mimic, although a much more exact mimic than is eRF1 (Fig. 2
; Selmer et al., 1999
). RRF-tRNA mimicry is almost certainly a central feature of its activity in dissociating ribosomes. It has been proposed that following termination and peptidyl release, RRF binds to the A-site and is translocated by EF-G in the same way as peptidyl-tRNA is translocated. P-site occupancy by RRF is then the trigger for ribosomal dissociation (Selmer et al., 1999
). This model has certain features which distinguish it from the proposal that IF3 acts to remove deacylated tRNA from the P-site following RRF-catalysed ribosome dissociation from the mRNA (Karimi et al., 1999
). However, it might be that in bacteria, post-termination mechanisms differ dependent upon the ribosome proximity to a ribosome-binding site (Selmer et al., 1999
).
The analogous ribosome recycling step in eukaryotes is in contrast completely uncharacterized; a homologous nucleus-encoded gene encoding an RRF-like protein is found in eukaryotes, but appears to be an organelle protein; in yeast, the RRF1 gene has a mitochondrial targeting sequence, and disruption of the gene is non-lethal, generating a petite phenotype typical of disrupted mitochondrial function (I. Stansfield & M. F. Tuite, unpublished). While other eukaryote RRF-encoding genes have been identified, they are all targeted to organelles such as chloroplasts (Rolland et al., 1999 ). No equivalent cytoplasmic form has yet been identified. One recent suggestion is that eRF3 may represent a combined RF3 and RRF activity, thus representing a eukaryote recycling function, although hard evidence to support this is lacking at present (Buckingham et al., 1997
).
Alternative post-termination events: resumed scanning
In eukaryotes, post-termination ribosomes can experience different fates, regulated by the nucleotide context of the stop codon. This is best exemplified by the post-transcriptional regulation mechanisms of the S. cerevisiae GCN4 gene, which encodes a transcription factor involved in responses to amino acid starvation. The GCN4 mRNA 5' UTR contains four uORFs, of which only uORF1 and uORF4 are required for wild-type translational control of GCN4 expression (Mueller & Hinnebusch, 1986 ). The precise details of this mechanism, and its relation to amino acid starvation responses, are reviewed elsewhere (Hinnebusch, 1997
). Of importance to this discussion of regulation of (post-) termination events are the findings that ribosomes can resume scanning after terminating translation at uORF1, and that they can subsequently acquire competence to reinitiate at downstream AUG codons (Hinnebusch, 1997
). In contrast, ribosomes terminating translation at the uORF4 termination codon are released from the mRNA (Abastado et al., 1991
; Dever et al., 1992
). This key difference between the behaviour of post-termination ribosomes at uORFs 1 and 4 results from the character of the nucleotide context immediately preceding (3 nt) and following (10 nt) the respective uORF stop codons (Grant & Hinnebusch, 1994
). An AU-rich nucleotide bias around the uORF1 stop codon triggers resumed scanning, whereas the GC-rich character of the corresponding uORF4 nucleotides promotes ribosome release and recycling. While the mechanism of action of these cis sequences is not fully understood, it is clear that no single sequence confers these properties, and that a wide variety of contexts can achieve the same effect (Grant & Hinnebusch, 1994
). uORFs in the 5' UTRs of the YAP1 and YAP2 genes, while having different sequences surrounding their stop codons, nevertheless have very similar properties to GCN4 uORFs 1 and 4, respectively, again an indication that primary sequence itself is not the prime determinant of the ability to promote resumed scanning (Vilela et al., 1998
). It has been suggested that the GC-rich environment around the uORF4 stop codon may pause a terminating ribosome (perhaps via rRNA interaction) long enough to allow a putative recycling factor to bind, an event prevented by rapid termination at uORF1 (Grant & Hinnebusch, 1994
). The region 5' of uORF1 is also important for the reinitiation stimulating ability of uORF1, although this mRNA region lies outside that which would be occluded by a ribosome terminating at uORF1 (Grant et al., 1995
).
In prokaryotic systems, small ORFs have peculiar properties, first highlighted by studies of the bar mini-genes, which encode dipeptides. During translation of such mini-genes, translation termination does not always take place, and in some instances, peptidyl-tRNA is released, stimulated by RRF, RF3 and the elongation factor EF-G; this reaction is detrimental to peptidyl hydrolase mutants expressing a mini-gene (peptidyl hydrolase breaks the tRNA nascent peptide bond in peptidyl tRNAs inappropriately released from the ribosome; Heurgue-Hamard et al., 1998
). Translation initiation factors IF1 and IF2 also play a role in stimulating release of nascent peptidyl-tRNA without a prior termination reaction during short ORF (mini-gene) translation in vitro, and in vivo, overexpression of IF1 and IF2 cause growth defects in a peptidyl hydrolase mutant (Karimi et al., 1998
). It is unclear at present whether these prokaryote termination-alternative reactions stimulated by mini-genes or uORFs have any significance for the regulatory properties conferred by uORF1 in the yeast GCN4 5' UTR. Certainly there is no direct evidence that translation termination actually takes place at either uORF 1 or uORF4, and the possibility that termination-alternative events take place has not been excluded.
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Conclusion and perspectives |
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RF-tRNA mimcry also raises some intriguing questions, at least in prokaryote systems, where apparently an EF-Tu like molecule is not required to bring the RF to the A-site (Freistroffer et al., 1997 ). What then provides the codonanticodon fidelity checking mechanism which is fulfilled by EF-Tu when an aminoacyl tRNA is presented to the A-site? Termination at non-stop codons occurs at very low frequencies, so fidelity is obviously preserved by some mechanism (Freistroffer et al., 2000
). It is also unclear how the release factors (which unlike tRNAs and EF-Tu/EF1-
, are present in the cell at relatively low abundance) are selected quickly by the ribosome when a stop codon is located at the A-site.
The use of reconstituted translation systems using highly purified protein trans-acting factors has allowed an increasingly detailed picture to emerge, not just of termination itself, but also of the events which follow it. Eukaryote termination is less well defined; although in vitro termination reactions have been reconstituted, the precise role of the GTPase eRF3 is unclear, and our knowledge of how eukaryote release factors are removed from the ribosome, and the ribosomes subsequently removed from the mRNA, are hazy. The need to recycle ribosomes or subunits back to the 5' end of the mRNA makes it likely that a specialized set of eukaryote factors exist for this purpose; either none have been identified to date, or factors already known have as yet undiscovered functions. The prospect of a fuller understanding emerging of the mechanism of both eukaryote and prokaryote termination in the near future is encouraging, providing a clear picture of how the last three codons in the genetic code are accurately decoded. It will also open the door to understanding how control of gene expression is exerted at the termination stage, and post-termination.
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ACKNOWLEDGEMENTS |
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