Sequence- And structure-specific cytosine-5 mRNA methylation by NSUN6

Tommaso Selmi, Shobbir Hussain, Sabine DIetmann, Matthias Heiß, Kayla Borland, Sophia Flad, Jean Michel Carter, Rebecca Dennison, Ya Lin Huang, Stefanie Kellner, Susanne Bornelöv, Michaela Frye

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


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.

Original languageEnglish
Pages (from-to)1006-1022
Number of pages17
JournalNucleic acids research
Issue number2
StatePublished - Jan 25 2021


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