Translation affects mRNA stability in a codon dependent manner in human cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA522258 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10348365.fastq.gz | Fastqsanger.gz | |||
| SRR10348366.fastq.gz | Fastqsanger.gz | |||
| SRR10348367.fastq.gz | Fastqsanger.gz | |||
| SRR10348368.fastq.gz | Fastqsanger.gz | |||
| SRR8571190.fastq.gz | Fastqsanger.gz |
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Project description:The reduced translation elongation rate caused by the presence of non-optimal codons can negatively impact mRNA stability through translation-dependent decay. A key aspect of this process is the coupling of sensing the mRNA codon usage with the regulation of translation efficiency and stability. We found that two paralog RNA-binding proteins; ZC3H7A and ZC3H7B; which have only emerged in Chordates, preferentially bind to and reduce the stability and translation of mRNAs enriched in the non-optimal codons with A/U at their wobble sites (A/U3 codons). ZC3H7A/B engage with ribosomes that lack elongation factors and induce mRNA degradation or block translation initiation through their interactions with the CCR4-NOT and the GIGYF2/4EHP translation repressor complex, respectively. Depletion of ZC3H7A and ZC3H7B or 4EHP impairs the repression of non-optimal A/U3-rich mRNAs. This study provides insights into a unique mechanism in higher eukaryotes that couples codon usage with the regulation of translation efficiency and mRNA stability.
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Project description:The reduced translation elongation rate caused by the presence of non-optimal codons can negatively impact mRNA stability through translation-dependent decay. A key aspect of this process is the coupling of sensing the mRNA codon usage with the regulation of translation efficiency and stability. We found that two paralog RNA-binding proteins; ZC3H7A and ZC3H7B; which have only emerged in Chordates, preferentially bind to and reduce the stability and translation of mRNAs enriched in the non-optimal codons with A/U at their wobble sites (A/U3 codons). ZC3H7A/B engage with ribosomes that lack elongation factors and induce mRNA degradation or block translation initiation through their interactions with the CCR4-NOT and the GIGYF2/4EHP translation repressor complex, respectively. Depletion of ZC3H7A and ZC3H7B or 4EHP impairs the repression of non-optimal A/U3-rich mRNAs. This study provides insights into a unique mechanism in higher eukaryotes that couples codon usage with the regulation of translation efficiency and mRNA stability.
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Project description:The reduced translation elongation rate caused by the presence of non-optimal codons can negatively impact mRNA stability through translation-dependent decay. A key aspect of this process is the coupling of sensing the mRNA codon usage with the regulation of translation efficiency and stability. We found that two paralog RNA-binding proteins; ZC3H7A and ZC3H7B; which have only emerged in Chordates, preferentially bind to and reduce the stability and translation of mRNAs enriched in the non-optimal codons with A/U at their wobble sites (A/U3 codons). ZC3H7A/B engage with ribosomes that lack elongation factors and induce mRNA degradation or block translation initiation through their interactions with the CCR4-NOT and the GIGYF2/4EHP translation repressor complex, respectively. Depletion of ZC3H7A and ZC3H7B or 4EHP impairs the repression of non-optimal A/U3-rich mRNAs. This study provides insights into a unique mechanism in higher eukaryotes that couples codon usage with the regulation of translation efficiency and mRNA stability.
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Project description:The reduced translation elongation rate caused by the presence of non-optimal codons can negatively impact mRNA stability through translation-dependent decay. A key aspect of this process is the coupling of sensing the mRNA codon usage with the regulation of translation efficiency and stability. We found that two paralog RNA-binding proteins; ZC3H7A and ZC3H7B; which have only emerged in Chordates, preferentially bind to and reduce the stability and translation of mRNAs enriched in the non-optimal codons with A/U at their wobble sites (A/U3 codons). ZC3H7A/B engage with ribosomes that lack elongation factors and induce mRNA degradation or block translation initiation through their interactions with the CCR4-NOT and the GIGYF2/4EHP translation repressor complex, respectively. Depletion of ZC3H7A and ZC3H7B or 4EHP impairs the repression of non-optimal A/U3-rich mRNAs. This study provides insights into a unique mechanism in higher eukaryotes that couples codon usage with the regulation of translation efficiency and mRNA stability.
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Project description:The control of mRNA stability plays a central role in regulating gene expression. In metazoans, the earliest stages of development are driven by maternally supplied mRNAs. The degradation of these maternal mRNAs is critical for promoting the maternal-to-zygotic transition of developmental programs, although the underlying mechanisms are poorly understood in vertebrates. Here, we characterized maternal mRNA degradation pathways in zebrafish using a transcriptome analysis and systematic reporter assays. Our data demonstrate that ORFs enriched with uncommon codons promote deadenylation by the CCR4-NOT complex in a translation-dependent manner. This codon-mediated mRNA decay is conditional on the context of the 3â² UTR, with long 3â² UTRs conferring resistance to deadenylation. These results indicate that the combined effect of codon usage and 3â² UTR length determines the stability of maternal mRNAs in zebrafish embryos. Our study thus highlights the codon-mediated mRNA decay as a conserved regulatory mechanism in eukaryotes. zebrafish embryonic mRNA profile at 2 different stages (2 hpf and 6 hpf) in wildtype and 3 additional conditions (miR-430 inhibition, RNApol II inhibition and CNOT7 inhibition) at 6 hpf. All experiments are performed as triplicates
2016-03-17 | E-GEOD-71609 | biostudies-arrayexpress
Project description: Not available
| S-EPMC6529216 | biostudies-literature
Project description:The control of mRNA stability plays a central role in regulating gene expression. In metazoans, the earliest stages of development are driven by maternally supplied mRNAs. The degradation of these maternal mRNAs is critical for promoting the maternal-to-zygotic transition of developmental programs, although the underlying mechanisms are poorly understood in vertebrates. Here, we characterized maternal mRNA degradation pathways in zebrafish using a transcriptome analysis and systematic reporter assays. Our data demonstrate that ORFs enriched with uncommon codons promote deadenylation by the CCR4-NOT complex in a translation-dependent manner. This codon-mediated mRNA decay is conditional on the context of the 3′ UTR, with long 3′ UTRs conferring resistance to deadenylation. These results indicate that the combined effect of codon usage and 3′ UTR length determines the stability of maternal mRNAs in zebrafish embryos. Our study thus highlights the codon-mediated mRNA decay as a conserved regulatory mechanism in eukaryotes.
2016-03-17 | GSE71609 | GEO
Project description:Ribosome profiling data reports on the distribution of translating ribosomes, at steady-state, with codon-level resolution. We present a robust method to extract codon translation rates and protein synthesis rates from these data, and identify causal features associated with elongation and translation efficiency in physiological conditions in yeast. We show that neither elongation rate nor translational efficiency is improved by experimental manipulation of the abundance or body sequence of the rare AGG tRNA. Deletion of three of the four copies of the heavily used ACA tRNA shows a modest efficiency decrease that could be explained by other rate-reducing signals at gene start. This suggests that correlation between codon bias and efficiency arises as selection for codons to utilize translation machinery efficiently in highly translated genes. We also show a correlation between efficiency and RNA structure calculated both computationally and from recent structure probing data, as well as the Kozak initiation motif, which may comprise a mechanism to regulate initiation. We test whether tRNA abundance affects elongation or translation efficiency by changing the tRNA levels through deletion or over expression and measuring the ribosomal dwell time at each codon using a robust statistical method that accounts for flow conservation.
2015-01-05 | E-GEOD-63789 | biostudies-arrayexpress
Project description:Codon usage bias is a universal feature of eukaryotic and prokaryotic genomes and has been proposed to regulate translation efficiency, accuracy and protein folding based on the assumption that codon usage affects translation dynamics. The role of codon usage in regulating translation, however, is not clear and has been challenged by recent ribosome profiling studies. Here we used a Neurospora cell-free translation system to directly monitor the velocity of mRNA translation. We demonstrated that the use of preferred codons enhances the rate of translation elongation, whereas non-optimal codons slow translation. In addition, codon usage regulates ribosome traffic on the mRNA. These conclusions were supported by ribosome profiling results in vitro and in vivo with substrate mRNAs manipulated to increase signal over background noise. We further show that codon usage plays an important role in regulating protein function by affecting co-translational protein folding. Together, these results resolve a long-standing fundamental question and demonstrate the importance of codon usage on protein folding.
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Project description:Reprogramming gene expression at the translational level drives intestinal tumorigenesis. Codon decoding during translation elongation relies on tRNA modifications, while their pathological relevance in colorectal cancer remains to be elucidated. Here, we show that AlkB homolog 8 (ALKBH8), a uridine 34 (U34) tRNA methyltransferase, is a direct target of Wnt/β-catenin and is upregulated in colorectal cancer. Genetic ablation of ALKBH8 inhibits the development of intestinal tumors in Apcmin/+, AOM/DSS, and xenograft models. Loss of ALKBH8 induces ribosome pausing at adenine-ending codons, impairing the translation elongation of mRNAs enriched with these codons. Specifically, ALKBH8 regulates the translation of KRAS proto-oncogene in a codon-dependent manner. Rescue experiments demonstrate that the methyltransferase activity of ALKBH8 is required for its translation-promoting function. Together, our findings reveal ALKBH8-dependent mRNA translation as a critical mediator of intestinal tumorigenesis, underscoring its potential as a promising target for colorectal cancer therapy.
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