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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 This article is categorized under: 1RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications2RNA Processing > Capping and 5' End Modifications3RNA in Disease and Development > RNA in Disease, 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

Human disc-large (hDlg) is a scaffold protein critical for the maintenance of cell polarity and adhesion. hDlg is a component of the p38γ MAP kinase pathway, which is important for the adaptation of mammalian cells to changes in environmental osmolarity. Here we report a strong decrease in the levels of hDlg protein in the human epithelial cell line HeLa when exposed to osmotic shock. This is independent of the phosphorylation state of hDlg, is prevented by preincubating the cell with the caspase inhibitor z-VAD and is part of the apoptotic process triggered by cellular stress. Although, both caspase 3 and caspase 6 are strongly activated by osmotic shock, the time course of caspase 6 activation parallels hDlg degradation, suggesting that this caspase may be responsible for the proteolysis. Mutating hDlg Asp747 to Ala abolishes caspase-induced cleavage, but does not affect the early stage of apoptosis or cell attachment. Our findings show that osmotic stress triggers hDlg degradation through a mechanism different from the one mediated by proteasomes, and we identify hDlg as a caspase substrate during the apoptotic process, although its proteolysis may not be implicated in the progression of early apoptosis.