Translational Efficiency of a Non-AUG Initiation Codon Is Significantly Affected by Its Sequence Context in Yeast

Chen, Shun Jia; Lin, Grace; Chang, Kuang Jung; Yeh, Lu Shu; Wang, Chien Chia

doi:10.1074/jbc.m706968200

Cited by 53 publications

(63 citation statements)

References 42 publications

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“…Finally, based on a high throughput screen of start codon context nucleotides, Dvir et al (2013) reported a significant, but modest (,30%), impact of a 23 purine on reporter gene expression. At odds with these studies, flanking nucleotides have been shown to be important in selection of the non-AUG start codon on the GRS1 mRNA (Chen et al 2008) as well as in the selection of alternate AUG start codons on the MOD5 and CCA1 mRNAs (Werner et al 1987;Slusher et al 1991;Wolfe et al 1994). In addition, the poor start codon context (C 23 GUAUG) of the SUI1 gene encoding translation factor eIF1 in yeast impairs expression and enables autoregulation due to the role of eIF1 in start codon selection (Martin-Marcos et al 2011).…”

Section: Mrna Features In Translation Initiationmentioning

confidence: 80%

“…Likewise, all possible single nucleotide substitutions at the AUG start codon of a HIS4-lacZ reporter lowered expression to #2% of the AUG control . However, the mRNAs encoding glycyl (Grs1) and alanyl (Ala1) tRNA synthetases initiate at both AUG and non-AUG codons (Chang and Wang 2004;Tang et al 2004;Chen et al 2008). Whereas the cytoplasmic synthetases initiate at an AUG start codon, the extended, mitochondrial enzymes initiate at upstream codons: UUG for Grs1 (Chen et al 2008) and ACG for Ala1 (Tang et al 2004).…”

Section: Mrna Features In Translation Initiationmentioning

confidence: 99%

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Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

2016

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In this review, we provide an overview of protein synthesis in the yeast Saccharomyces cerevisiae. The mechanism of protein synthesis is well conserved between yeast and other eukaryotes, and molecular genetic studies in budding yeast have provided critical insights into the fundamental process of translation as well as its regulation. The review focuses on the initiation and elongation phases of protein synthesis with descriptions of the roles of translation initiation and elongation factors that assist the ribosome in binding the messenger RNA (mRNA), selecting the start codon, and synthesizing the polypeptide. We also examine mechanisms of translational control highlighting the mRNA cap-binding proteins and the regulation of GCN4 and CPA1 mRNAs.

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Section: Mrna Features In Translation Initiationmentioning

confidence: 80%

Section: Mrna Features In Translation Initiationmentioning

confidence: 99%

Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

2016

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“…Adenines at positions Ϫ3 to Ϫ1 relative to AUG are highly preferred among genes in Saccharomyces species (44), and there is evidence that A Ϫ3 -A Ϫ2 -(A/G) Ϫ1 -AUG is the optimal context for initiation in Saccharomyces cerevisiae (7). Saccharomyces species resemble other eukaryotes in displaying poor context for the AUG codon at the eIF1 gene (SUI1), C Ϫ3 -G Ϫ2 -U Ϫ1 -AUG, which matches at Ϫ3 and Ϫ2 a highly unfavorable sequence context identified in S. cerevisiae, of C Ϫ3 -G Ϫ2 -C Ϫ1 -AUG (7).…”

Section: Metmentioning

confidence: 99%

Functional Elements in Initiation Factors 1, 1A, and 2β Discriminate against Poor AUG Context and Non-AUG Start Codons

Martín-Marcos

Cheung

Hinnebusch

2011

Molecular and Cellular Biology

136

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Yeast eIF1 inhibits initiation at non-AUG triplets, but it was unknown whether it also discriminates against AUGs in suboptimal context. As in other eukaryotes, the yeast gene encoding eIF1 (SUI1) contains an AUG in poor context, which could underlie translational autoregulation. Previously, eIF1 mutations were identified that increase initiation at UUG codons (Sui ؊ phenotype), and we obtained mutations with the opposite phenotype of suppressing UUG initiation (Ssu ؊ phenotype). Remarkably, Sui ؊ mutations in eukaryotic translation initiation factor 1 (eIF1), eIF1A, and eIF2␤ all increase SUI1 expression in a manner diminished by introducing the optimal context at the SUI1 AUG, whereas Ssu ؊ mutations in eIF1 and eIF1A decrease SUI1 expression with the native, but not optimal, context present. Therefore, discrimination against weak context depends on specific residues in eIFs 1, 1A, and 2␤ that also impede selection of non-AUGs, suggesting that context nucleotides and AUG act coordinately to stabilize the preinitiation complex. Although eIF1 autoregulates by discriminating against poor context in yeast and mammals, this mechanism does not prevent eIF1 overproduction in yeast, accounting for the hyperaccuracy phenotype afforded by SUI1 overexpression.Bacterial translation initiation factor 3 (IF3) promotes the fidelity of initiation at AUG codons by discriminating against non-AUG triplets as start sites (17,26,40,45). This discriminatory function forms the basis for IF3's ability to negatively autoregulate translation of its mRNA, which initiates with an AUU start codon (5, 6). IF3 also destabilizes initiation complexes formed on AUG codons at the 5Ј ends of leaderless mRNAs (47), which lack the Shine-Dalgarno sequence that stabilizes mRNA association with the small (30S) ribosomal subunit at the AUG codon.In eukaryotes, the 43S preinitiation complex (PIC), harboring the eIF2-GTP-Met-tRNA i Met ternary complex (TC) and various other eIFs, attaches to the capped 5Ј end of the mRNA and identifies the AUG codon by scanning the mRNA leader base-by-base for complementarity with the anticodon of MettRNA i Met. Efficient initiation is influenced by the sequence immediately upstream from the AUG, but it is unclear how this sequence context is recognized or regulates AUG selection (20,36). The functional counterpart of IF3 in eukaryotes appears to be eIF1 (Sui1 in yeast). eIF1 and IF3 occupy analogous locations on the platform of the small ribosomal subunit (11,27,38) and, similar to IF3, eIF1 blocks formation of stable 48S PICs at near-cognate start codons (20, 36). eIF1/Sui1 and eIF1A (Tif11 in yeast) cooperate to promote an open conformation of the 40S subunit (34) thought to be conducive to scanning (35), and eIF1 also blocks the final step of GTP hydrolysis by the TC, the release of P i from eIF2-GDP-P i , until an AUG enters the P site (1). AUG recognition triggers dissociation of eIF1 from the 40S subunit (30), enabling P i release and stabilizing a closed conformation of the 40S subunit that is incompatible with ...

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“…Nonetheless, three yeast genes, GRS1 (one of the two glycyl-tRNA synthetase (GlyRS) genes in S. cerevisiae) (11), ALA1 (the only alanyl-tRNA synthetase (AlaRS) gene in S. cerevisiae) (12), and CARP2A (the gene coding for acidic ribosomal protein P2A in Candida albicans) (25), have recently been reported to use naturally occurring non-AUG triplets as translation initiators. Moreover, a very recent study suggested that the translational efficiency of non-AUG initiation codons is significantly affected (up to 32-fold) by nucleotides at its relative Ϫ3 to Ϫ1 position, and, to a lesser extent, ϩ4 (26). The nucleotide at position Ϫ3 is the most influential one.…”

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confidence: 99%

“…The nucleotide at position Ϫ3 is the most influential one. AARuugA (R represents A or G; uug represents a non-AUG initiation codon) appears to be the most favorable sequence context for a non-AUG initiation site (26).…”

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confidence: 99%

Translational Efficiency of Redundant ACG Initiator Codons Is Enhanced by a Favorable Sequence Context and Remedial Initiation

Chen

Yen

et al. 2009

Journal of Biological Chemistry

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Earlier studies showed that the redundancy of ACG initiation codons enhanced the efficiency of translation initiation by 3-to 6-fold. Evidence presented here shows that this "redundancy effect" can be attributed to a favorable sequence context and, to a lesser extent, remedial initiation. In the case of redundant ACG initiator codons, the second ACG not only acts as a remedial initiation site for scanning ribosomes that skip the first ACG but also enhances the activity of the preceding initiator by providing a preferable "A" at its relative ؉4 position. Hence, nonsuccessive ACG codons can be as effective as successive ACG codons in initiation, if positioned within a similar context. In contrast, redundant GUG initiation codons (GUG/GUG) bear an unfavorable "G" nucleotide at both the ؉4 and ؊3 positions relative to the first and second GUGs, respectively, such that redundant GUG codons act more poorly as translation initiation sites than does a single GUG with a favorable "A" nucleotide in the ؉4 position (ϳ2.5-fold). Thus, the sequence context plays a much more important role than remedial initiation in modulating the efficiency of translational initiation from redundant non-AUG codons.

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Translational Efficiency of a Non-AUG Initiation Codon Is Significantly Affected by Its Sequence Context in Yeast

Cited by 53 publications

References 42 publications

Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

Functional Elements in Initiation Factors 1, 1A, and 2β Discriminate against Poor AUG Context and Non-AUG Start Codons

Translational Efficiency of Redundant ACG Initiator Codons Is Enhanced by a Favorable Sequence Context and Remedial Initiation

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