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Sequence- and structure-specific cytosine-5 mRNA methylation by NSUN6.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Selmi, Tommaso 
Hussain, Shobbir 
Dietmann, Sabine 
Heiß, Matthias 
Borland, Kayla 

Abstract

The highly abundant N6-methyladenosine (m6A) RNA modification affects most aspects of mRNA function, yet the precise function of the rarer 5-methylcytidine (m5C) remains largely unknown. Here, we map m5C in the human transcriptome using methylation-dependent individual-nucleotide resolution cross-linking 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.

Description

Keywords

3' Untranslated Regions, Animals, Base Sequence, Cell Line, Tumor, Codon Usage, Consensus Sequence, Cytidine, Embryonic Stem Cells, Gene Knockout Techniques, Genes, Reporter, HEK293 Cells, Humans, Immunoprecipitation, Methylation, Mice, Mice, Knockout, Mutagenesis, Site-Directed, RNA Processing, Post-Transcriptional, RNA, Messenger, Transcriptome, tRNA Methyltransferases

Journal Title

Nucleic Acids Res

Conference Name

Journal ISSN

0305-1048
1362-4962

Volume Title

49

Publisher

Oxford University Press (OUP)
Sponsorship
Wellcome Trust (203151/Z/16/Z)
Medical Research Council (MC_PC_17230)
Cancer Research Uk (None)
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