Regulation and function of CMTR1-dependent mRNA cap methylation

Abstract

mRNA is modified co-transcriptionally at the 5' end by the addition of an inverted guanosine cap structure which can be methylated at several positions. The mRNA cap recruits proteins involved in gene expression and identifies the transcript as being cellular or 'self' in the innate immune response. Methylation of the first transcribed nucleotide on the ribose 2'-O position is a prevalent cap modification which has roles in splicing, translation and provides protection against the innate immune response. In this review, we discuss the regulation and function of CMTR1, the first transcribed nucleotide ribose 2'-O methyltransferase, and the molecular interactions which mediate methylated 2'-O ribose function. WIREs RNA 2017, 8:e1450. doi: 10.1002/wrna.1450 For further resources related to this article, please visit the WIREs website.

Figure 1

CMTR1 functional domains. NLS, nuclear localization signal; G‐patch, glycine rich domain; RFM, Rossman‐fold methyltransferase domain; GT‐like, guanylyltransferase‐like domain; WW, protein interaction domain; phos, amino acid 28–66 multiple phosphorylation sites (sites with more than five references in phosphosite plus).37, 38

Figure 2

‘Self’‐RNA recognition and immune tolerence to 2′‐O methylated RNA. CMTR1 and viral methyltransferases (Mtases) catalyse first nucleotide ribose 2′‐O methylation, which prevents transcript recognition by RIG‐I or MDA5. In the absence of ribose 2′‐O methylation, RIG‐I or MDA5 elicit the interferon response which includes expression of IFIT proteins. IFIT1 binds to transcripts unmethylated on ribose 2′‐O to inhibit translation. m⁷GpppN, 7′‐N cap (N, first nucleotide); m, ribose 2′‐O methylation; Green lines, activity or permissive effect; Black line, binding and repression; Grey dotted lines, absence of translation.