Initiation context modulates autoregulation of eukaryotic translation initiation factor 1 (eIF1)

Ivanov, Ivaylo P.; Loughran, Gary; Sachs, Matthew S.; Atkins, John F.

doi:10.1073/pnas.1009269107

Cited by 132 publications

(199 citation statements)

References 33 publications

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“…Using a reconstituted in vitro system, it was demonstrated that mammalian eIF1 can discriminate against AUGs in suboptimal context in addition to preventing recognition of non-AUG codons (35), and it was envisioned that context nucleotides help to stabilize the closed conformation of the PIC that is competent for start codon recognition (37). As first proposed by Ivanov et al (22), its ability to discriminate against poor AUG context would allow mammalian eIF1 to negatively autoregulate translation by discriminating against the poor context of its start codon and, while our work was under way, these researchers provided strong evidence that this autoregulatory mechanism indeed operates in mammalian cells.…”

Section: Metmentioning

confidence: 89%

“…It was reported recently that the genes encoding eIF1 in diverse eukaryotes contain an AUG context that deviates significantly from that found at highly expressed genes (22,31). In particular, eIF1 genes generally contain pyrimidines rather than purines at the Ϫ3 position, shown by Kozak to be the most critical contextual determinant of AUG selection in mammals (24).…”

Section: Metmentioning

confidence: 99%

“…In comparing these results to ours, it appears that eIF1 is more effective in discriminating against poor context in mammalian cells than in yeast, as the SUI1-lacZ reporter with native context was repressed by only a factor of 2 in response to highlevel eIF1 overexpression in yeast. As a consequence, eIF1 is substantially overexpressed in cells harboring the hc SUI1 plasmid (with the native, poor context), whereas overexpression of eIF1 in mammalian cells was achieved only by introducing additional copies of the EIF1 gene modified to contain the optimal Kozak consensus sequence (22). Moreover, replacing the native EIF1 context with the optimal Kozak consensus increased reporter expression by a factor of 4, while the comparable replacement in yeast increased SUI1-lacZ expression by only a factor of ϳ2.…”

Section: Metmentioning

confidence: 99%

“…It was demonstrated recently that eIF1 discriminates against poor AUG context in mammalian cells, such that eIF1 overexpression specifically repressed by a factor of ϳ5 the expression of luciferase reporters lacking both critical residues of the optimal "Kozak" consensus (purine at Ϫ3 and G at ϩ4) (24) and repressed by an order of magnitude a reporter gene containing the poor consensus found at the native gene encoding eIF1 (EIF1) (22). This repressive function underlies the robust autoregulation of EIF1 expression in mammalian cells.…”

Section: Metmentioning

confidence: 99%

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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

135

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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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Section: Metmentioning

confidence: 89%

Section: Metmentioning

confidence: 99%

Section: Metmentioning

confidence: 99%

Section: Metmentioning

confidence: 99%

See 2 more Smart Citations

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

135

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“…The majority of our detected uORFs had no AUG start codons. eIF1 and eIF5 are the factors that control the recognition of start codons during translation initiation in eukaryotes (25,26). We suggest that hydrogen peroxide impairs the fidelity of these factors, which normally restrict initiation to AUG codons, thereby facilitating non-AUG initiation of translation as the ribosome scans the mRNA.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide ribosome profiling reveals complex translational regulation in response to oxidative stress

Gerashchenko

Lobanov

Gladyshev

2012

Proc. Natl. Acad. Sci. U.S.A.

272

290

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Information on unique and coordinated regulation of transcription and translation in response to stress is central to the understanding of cellular homeostasis. Here we used ribosome profiling coupled with next-generation sequencing to examine the interplay between transcription and translation under conditions of hydrogen peroxide treatment in Saccharomyces cerevisiae . Hydrogen peroxide treatment led to a massive and rapid increase in ribosome occupancy of short upstream ORFs, including those with non-AUG translational starts, and of the N-terminal regions of ORFs that preceded the transcriptional response. In addition, this treatment induced the synthesis of N-terminally extended proteins and elevated stop codon read-through and frameshift events. It also increased ribosome occupancy at the beginning of ORFs and potentially the duration of the elongation step. We identified proteins whose synthesis was regulated rapidly by hydrogen peroxide posttranscriptionally; however, for the majority of genes increased protein synthesis followed transcriptional regulation. These data define the landscape of genome-wide regulation of translation in response to hydrogen peroxide and suggest that potentiation (coregulation of the transcript level and translation) is a feature of oxidative stress.

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Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease

Fernandes

Romão

2020

Encyclopedia of Life Sciences

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Upstream open reading frames (uORFs) are cis ‐acting elements, located before or overlapped with the main coding ORF (mORF), that regulate cap‐dependent translation efficiency in a transcript‐specific manner. More than half of the human transcripts bear at least one uORF. In addition, it has been recently revealed that many of these uORFs initiate at non‐AUG codons, which significantly increases the complexity and diversity of the human translatome. These regulons are considered repressors of downstream translation but, in some biological contexts, they induce mORF expression. There are several the mechanisms by which AUG and non‐AUG uORFs regulate gene expression, allowing the cell to control transcript‐specific translation according to its needs. Also, we describe several examples of uORF genetic variants associated with human genetic diseases. Studying these cases and understanding the resultant abnormal mechanisms of uORF‐mediated translational control is of extreme importance for the development of new therapeutic strategies. Key Concepts Upstream open reading frames (uORFs) are cis ‐acting translational regulatory elements present within the 5′ leader sequence of mRNAs. uORFs can regulate gene expression by repressing or promoting translation of the downstream main ORF (mORF), according to the cellular environment. The number of uORFs, the intercistronic distance, the overlap with the mORF and the context of the initiation codon are the uORF‐related structural features that most influence their translational regulatory capacity. uORF‐mediated repression of mORF translation is usually achieved by ribosome dissociation, ribosome stalling, induction of nonsense‐mediated mRNA decay (NMD) or production of inhibitory peptides. uORF‐mediated induction of mORF translation is usually achieved by ribosome bypass or translation reinitiation. uORFs initiated by non‐AUG codons are more frequent than previously appreciated, having important biological functions. uORF‐altering polymorphisms and mutations, which create, disrupt or change a uORF, can cause human genetic diseases. Studying and understanding the uORF‐mediated mechanisms of gene expression regulation may provide knowledge to develop novel therapies for several human diseases.

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Initiation context modulates autoregulation of eukaryotic translation initiation factor 1 (eIF1)

Cited by 132 publications

References 33 publications

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

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

Genome-wide ribosome profiling reveals complex translational regulation in response to oxidative stress

Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease

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