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Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132010 | GEO | 2019/12/03

REPOSITORIES: GEO

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Suppression of Ribosomal Pausing by eIF5A Is Necessary to Maintain the Fidelity of Start Codon Selection.

Project description:Sequences within 5' UTRs dictate the site and efficiency of translation initiation. In this study, an unbiased screen designed to interrogate the 5' UTR-mediated regulation of the growth-promoting gene MYC unexpectedly revealed the ribosomal pause relief factor eIF5A as a regulator of translation initiation codon selection. Depletion of eIF5A enhances upstream translation within 5' UTRs across yeast and human transcriptomes, including on the MYC transcript, where this results in increased production of an N-terminally extended protein. Furthermore, ribosome profiling experiments established that the function of eIF5A as a suppressor of ribosomal pausing at sites of suboptimal peptide bond formation is conserved in human cells. We present evidence that proximal ribosomal pausing on a transcript triggers enhanced use of upstream suboptimal or non-canonical initiation codons. Thus, we propose that eIF5A functions not only to maintain efficient translation elongation in eukaryotic cells but also to maintain the fidelity of translation initiation.

| S-EPMC6917043 | biostudies-literature

Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection (CRISPR screen)

Project description:Sequences within 5' untranslated regions (UTRs) dictate the site and efficiency of translation initiation. In this study, an unbiased screen designed to interrogate the 5' UTR-mediated regulation of the growth-promoting gene MYC unexpectedly revealed the ribosomal pause-relief factor eIF5A as a regulator of translation initiation codon selection. Depletion of eIF5A enhanced upstream translation within 5' UTRs across yeast and human transcriptomes, including on the MYC transcript where this resulted in increased production of an N-terminally extended protein. Furthermore, ribosome profiling experiments established that the function of eIF5A as a suppressor of ribosomal pausing at sites of suboptimal peptide bond formation is conserved in human cells. We present evidence that proximal ribosomal pausing on a transcript triggers enhanced usage of upstream suboptimal or non-canonical initiation codons. Thus, we propose that eIF5A functions not only to maintain efficient translation elongation in eukaryotic cells, but also to maintain the fidelity of translation initiation.

2019-12-03 | GSE132009 | GEO

Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection (RNA-sequencing)

2019-12-03 | GSE132008 | GEO

Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection (Ribosome profiling)

2019-12-03 | GSE132007 | GEO

Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection

Project description:Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection

| PRJNA545619 | ENA

Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection (CRISPR screen)

Project description:Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection (CRISPR screen)

| PRJNA545621 | ENA

Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection (RNA-sequencing)

Project description:Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection (RNA-sequencing)

| PRJNA545624 | ENA

Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection (Ribosome profiling)

Project description:Suppression of ribosomal pausing by eIF5A is necessary to maintain the fidelity of start codon selection (Ribosome profiling)

| PRJNA545625 | ENA

N- and C-terminal residues of eIF1A have opposing effects on the fidelity of start codon selection.

Project description:Translation initiation factor eIF1A stimulates preinitiation complex (PIC) assembly and scanning, but the molecular mechanisms of its functions are not understood. We show that the F131A,F133A mutation in the C-terminal tail (CTT) of eIF1A impairs recruitment of the eIF2-GTP-Met-tRNA(i)(Met) ternary complex to 40S subunits, eliminating functional coupling with eIF1. Mutating residues 17-21 in the N-terminal tail (NTT) of eIF1A also reduces PIC assembly, but in a manner rescued by eIF1. Interestingly, the 131,133 CTT mutation enhances initiation at UUG codons (Sui(-) phenotype) and decreases leaky scanning at AUG, while the NTT mutation 17-21 suppresses the Sui(-) phenotypes of eIF5 and eIF2beta mutations and increases leaky scanning. These findings and the opposite effects of the mutations on eIF1A binding to reconstituted PICs suggest that the NTT mutations promote an open, scanning-conducive conformation of the PIC, whereas the CTT mutations 131,133 have the reverse effect. We conclude that tight binding of eIF1A to the PIC is an important determinant of AUG selection and is modulated in opposite directions by residues in the NTT and CTT of eIF1A.

| S-EPMC1829380 | biostudies-literature

Dissociation of eIF1 from the 40S ribosomal subunit is a key step in start codon selection in vivo.

Project description:Selection of the AUG start codon is a key step in translation initiation requiring hydrolysis of GTP in the eIF2*GTP*Met-tRNA(i)(Met) ternary complex (TC) and subsequent P(i) release from eIF2*GDP*P(i). It is thought that eIF1 prevents recognition of non-AUGs by promoting scanning and blocking P(i) release at non-AUG codons. We show that Sui(-) mutations in Saccharomyces cerevisiae eIF1, which increase initiation at UUG codons, reduce interaction of eIF1 with 40S subunits in vitro and in vivo, and both defects are diminished in cells by overexpressing the mutant proteins. Remarkably, Sui(-) mutation ISQLG(93-97)ASQAA (abbreviated 93-97) accelerates eIF1 dissociation and P(i) release from reconstituted preinitiation complexes (PICs), whereas a hyperaccuracy mutation in eIF1A (that suppresses Sui(-) mutations) decreases the eIF1 off-rate. These findings demonstrate that eIF1 dissociation is a critical step in start codon selection, which is modulated by eIF1A. We also describe Gcd(-) mutations in eIF1 that impair TC loading on 40S subunits or destabilize the multifactor complex containing eIF1, eIF3, eIF5, and TC, showing that eIF1 promotes PIC assembly in vivo beyond its important functions in AUG selection.

| S-EPMC1865493 | biostudies-literature

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