TRNA modification landscape selectively controls mitochondrial translation efficiency in MERRF
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ABSTRACT:
PROVIDER: PRJNA417375 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6263220_1.fastq.gz | Fastqsanger.gz | |||
| SRR6263220_2.fastq.gz | Fastqsanger.gz | |||
| SRR6263221_1.fastq.gz | Fastqsanger.gz | |||
| SRR6263221_2.fastq.gz | Fastqsanger.gz | |||
| SRR6263222_1.fastq.gz | Fastqsanger.gz |
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Project description:The cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, while the underlying mechanisms are poorly understood. N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex METTL1/WDR4 are significantly up-regulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We developed tRNA reduction and cleavage sequencing (TRAC-Seq) to reveal the m7G tRNA methylome inICC cell line and ribosome nascent-chain complex-bound mRNAs sequencing(RNC-seq) and ribosome profiling(Ribo-seq) to study the differential translated genes and reveal the ribosome pausing. A subset of 22 tRNAs is modified at a ‘RAGGU’ motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in the Mettl1 knockdown ICC cell line implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and EGFR signaling pathway genes is particularly affected. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of cancer progression.
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Project description:N6-methyladenosine (m6A) is the most abundant internal messenger (mRNA) modification in mammalian mRNA. This modification is reversible and non-stoichiometric, which potentially adds an additional layer of variety and dynamic control of mRNA metabolism. The m6A-modified mRNA can be selectively recognized by the YTH family “reader” proteins. The preferential binding of m6A-containing mRNA by YTHDF2 is known to reduce the stability of the target transcripts; however, the exact effects of m6A on translation has yet to be elucidated. Here we show that another m6A reader protein, YTHDF1, promotes ribosome loading of its target transcripts. YTHDF1 forms a complex with translation initiation factors to elevate the translation efficiency of its bound mRNA. In a unified mechanism of translation control through m6A, the YTHDF2-mediated decay controls the lifetime of target transcripts; whereas, the YTHDF1-based translation promotion increases the translation efficiency to ensure effective protein production from relatively short-lived transcripts that are marked by m6A. PAR-CLIP and RIP was used to identify YTHDF1 binding sites followed by ribosome profling and RNA seq to assess the consequences of YTHDF1 siRNA knock-down
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Project description:N6-methyladenosine (m6A) is the most abundant internal messenger (mRNA) modification in mammalian mRNA. This modification is reversible and non-stoichiometric, which potentially adds an additional layer of variety and dynamic control of mRNA metabolism. The m6A-modified mRNA can be selectively recognized by the YTH family “reader” proteins. The preferential binding of m6A-containing mRNA by YTHDF2 is known to reduce the stability of the target transcripts; however, the exact effects of m6A on translation has yet to be elucidated. Here we show that another m6A reader protein, YTHDF1, promotes ribosome loading of its target transcripts. YTHDF1 forms a complex with translation initiation factors to elevate the translation efficiency of its bound mRNA. In a unified mechanism of translation control through m6A, the YTHDF2-mediated decay controls the lifetime of target transcripts; whereas, the YTHDF1-based translation promotion increases the translation efficiency to ensure effective protein production from relatively short-lived transcripts that are marked by m6A.
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