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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132007 | 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 (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.

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

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Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s Disease

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Initiation Pausing of 80S Ribosome on mRNA Is Governed by 5'UTR and Responsive to mTORC1 Signaling (RNA-Seq)

Project description:Recent studies have revealed that the mRNA translation is punctuated by ribosomal pauses through the body of transcripts. However, little is known about its physiological significance and regulatory aspects. Here we present a multi-dimensional ribosome profiling approach to quantify the dynamics of initiation and elongation of 80S ribosomes across the entire transcriptome in mammalian cells. We show that a subset of transcripts have a significant pausing of 80S ribosome around the start codon, creating a major barrier to the commitment of translation elongation. Intriguingly, genes encoding ribosome proteins themselves exhibit an exceptionally high initiation pausing on their transcripts. Our studies also reveal that the initiation pausing is dependent on the 5M-bM-^@M-^Y untranslated region (5M-bM-^@M-^Y UTR) of mRNAs and subject to the regulation of mammalian target of rapamycin complex 1 (mTORC1). Thus, the initiation pausing of 80S ribosome represents a novel regulatory step in translational control mediated by nutrient signaling pathway. Monitor the translational status of transcriptome in mammalian cells under different conditions

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The RNA helicase Ded1p suppresses translation initiation from near-cognate start codons

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Initiation Pausing of 80S Ribosome on mRNA Is Governed by 5’UTR and Responsive to mTORC1 Signaling

Project description:This SuperSeries is composed of the following subset Series: GSE25331: Initiation pausing of mRNA translation controlled by mTORC1 signaling (microarray) GSE25626: Initiation pausing of mRNA translation controlled by mTORC1 signaling (RNA-Seq) Refer to individual Series

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Initiation Pausing of 80S Ribosome on mRNA Is Governed by 5’UTR and Responsive to mTORC1 Signaling (Microarray)

Project description:Recent studies have revealed that the mRNA translation is punctuated by ribosomal pauses through the body of transcripts. However, little is known about its physiological significance and regulatory aspects. Here we present a multi-dimensional ribosome profiling approach to quantify the dynamics of initiation and elongation of 80S ribosomes across the entire transcriptome in mammalian cells. We show that a subset of transcripts have a significant pausing of 80S ribosome around the start codon, creating a major barrier to the commitment of translation elongation. Intriguingly, genes encoding ribosome proteins themselves exhibit an exceptionally high initiation pausing on their transcripts. Our studies also reveal that the initiation pausing is dependent on the 5’ untranslated region (5’ UTR) of mRNAs and subject to the regulation of mammalian target of rapamycin complex 1 (mTORC1). Thus, the initiation pausing of 80S ribosome represents a novel regulatory step in translational control mediated by nutrient signaling pathway. Untreated TSC2 WT MEFs, TSC2 KO MEFs and TSC2 WT MEFs, TSC2 KO MEFs treated with 20nM rapamycin for 30 minutes or 3hours were harvested for ribosme profiling. The fraction samples were pooled into three groups based on velocity sedimentation: single ribosome fraction (Small group), fractions with 2 ~ 4 ribosomes (Medium group), and the one with ≥5 ribosomes (Large group). RNA were extracted from the whole cell lysis and each fraction group.

2011-11-12 | E-GEOD-25331 | biostudies-arrayexpress

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

Initiation Pausing of 80S Ribosome on mRNA Is Governed by 5'UTR and Responsive to mTORC1 Signaling (RNA-Seq)

Project description:Recent studies have revealed that the mRNA translation is punctuated by ribosomal pauses through the body of transcripts. However, little is known about its physiological significance and regulatory aspects. Here we present a multi-dimensional ribosome profiling approach to quantify the dynamics of initiation and elongation of 80S ribosomes across the entire transcriptome in mammalian cells. We show that a subset of transcripts have a significant pausing of 80S ribosome around the start codon, creating a major barrier to the commitment of translation elongation. Intriguingly, genes encoding ribosome proteins themselves exhibit an exceptionally high initiation pausing on their transcripts. Our studies also reveal that the initiation pausing is dependent on the 5’ untranslated region (5’ UTR) of mRNAs and subject to the regulation of mammalian target of rapamycin complex 1 (mTORC1). Thus, the initiation pausing of 80S ribosome represents a novel regulatory step in translational control mediated by nutrient signaling pathway.

2011-11-12 | GSE25626 | GEO

Initiation Pausing of 80S Ribosome on mRNA Is Governed by 5’UTR and Responsive to mTORC1 Signaling (Microarray)

Project description:Recent studies have revealed that the mRNA translation is punctuated by ribosomal pauses through the body of transcripts. However, little is known about its physiological significance and regulatory aspects. Here we present a multi-dimensional ribosome profiling approach to quantify the dynamics of initiation and elongation of 80S ribosomes across the entire transcriptome in mammalian cells. We show that a subset of transcripts have a significant pausing of 80S ribosome around the start codon, creating a major barrier to the commitment of translation elongation. Intriguingly, genes encoding ribosome proteins themselves exhibit an exceptionally high initiation pausing on their transcripts. Our studies also reveal that the initiation pausing is dependent on the 5’ untranslated region (5’ UTR) of mRNAs and subject to the regulation of mammalian target of rapamycin complex 1 (mTORC1). Thus, the initiation pausing of 80S ribosome represents a novel regulatory step in translational control mediated by nutrient signaling pathway.

2011-11-12 | GSE25331 | GEO

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