期刊
NUCLEIC ACIDS RESEARCH
卷 49, 期 2, 页码 -出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkaa1193
关键词
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资金
- Cancer Research UK(CR-UK)
- Medical Research Council (MRC)
- European Research Council (ERC)
- Wellcome
- MRC
- Biotechnology and Biological Sciences Research Council (BBSRC)
- DKFZ
- BBSRC [BB/N000749/1] Funding Source: UKRI
The study identifies NSUN6 as a methyltransferase targeting mRNA, primarily in 3'UTRs, involved in translation termination fidelity as part of a quality control mechanism.
The highly abundant N6-methyladenosine (m(6)A) RNA modification affects most aspects of mRNA function, yet the precise function of the rarer 5-methylcytidine (m(5)C) remains largely unknown. Here, we map m(5)C in the human transcriptome using methylationdependent individual-nucleotide resolution crosslinking and immunoprecipitation (miCLIP) combined with RNA bisulfite sequencing. We identify NSUN6 as a methyltransferase with strong substrate specificity towards mRNA. NSUN6 primarily targeted three prime untranslated regions (3'UTR) at the consensus sequence motif CTCCA, located in loops of hairpin structures. Knockout and rescue experiments revealed enhanced mRNA and translation levels when NSUN6-targeted mRNAs were methylated. Ribosome profiling further demonstrated that NSUN6-specific methylation correlated with translation termination. While NSUN6 was dispensable for mouse embryonic development, it was down-regulated in human tumours and high expression of NSUN6 indicated better patient outcome of certain cancer types. In summary, our study identifies NSUN6 as a methyltransferase targeting mRNA, potentially as part of a quality control mechanism involved in translation termination fidelity.
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