Sequence- and structure-specific cytosine-5 mRNA methylation by NSUN6. Issue 2 (16th December 2020)

• Record Type: Journal Article
• Authors: Selmi, Tommaso; Hussain, Shobbir; Dietmann, Sabine; Heiß, Matthias; Borland, Kayla; Flad, Sophia; Carter, Jean-Michel; Dennison, Rebecca; Huang, Ya-Lin; Kellner, Stefanie; Bornelöv, Susanne; Frye, Michaela
• Is Part Of: Nucleic acids research. Volume 49:Issue 2(2021)
• Page Start: 1006
• Page End: 1022
• Publication Date: 2020-12-16
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkaa1193
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: 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 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.