2′-O-ribose methylation of cap2 in human: function and evolution in a horizontally mobile family

Abstract

The 5′ cap of human messenger RNA consists of an inverted 7-methylguanosine linked to the first transcribed nucleotide by a unique 5′–5′ triphosphate bond followed by 2′-O-ribose methylation of the first and often the second transcribed nucleotides, likely serving to modify efficiency of transcript processing, translation and stability. We report the validation of a human enzyme that methylates the ribose of the second transcribed nucleotide encoded by FTSJD1, henceforth renamed HMTR2 to reflect function. Purified recombinant hMTr2 protein transfers a methyl group from S-adenosylmethionine to the 2′-O-ribose of the second nucleotide of messenger RNA and small nuclear RNA. Neither N7 methylation of the guanosine cap nor 2′-O-ribose methylation of the first transcribed nucleotide are required for hMTr2, but the presence of cap1 methylation increases hMTr2 activity. The hMTr2 protein is distributed throughout the nucleus and cytosol, in contrast to the nuclear hMTr1. The details of how and why specific transcripts undergo modification with these ribose methylations remains to be elucidated. The 2′-O-ribose RNA cap methyltransferases are present in varying combinations in most eukaryotic and many viral genomes. With the capping enzymes in hand their biological purpose can be ascertained.

The Frustrated Gene: Origins of Eukaryotic Gene Expression

“…The 2′- O -methylation of riboses near the 5′ ends of eukaryotic mRNAs serve as additional signals to distinguish normal uncapped cellular pre-mRNAs from viral RNAs (Daffis et al, 2010). Interestingly, the evolution of the eukaryotic cap methylation machinery appears to have involved horizontal gene transfer between eukaryotes and viruses, supporting the possibility of conflict between host and viruses with respect to these sugar modifications of mRNA (Werner et al, 2011). …”

Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability

“…In higher eukaryotes, additional methylation of mRNA occurs at the 2 ′ -O position of the first ribose sugar (m 7 GpppNm, cap 1 structure) via a nuclear 2 ′ -O methyltransferase enzyme. Because some IFIT family members (e.g., mouse Ifit1) directly recognize cap 0 RNA, host 2 ′ -O methylation serves to distinguish self and non-self RNA (Daffis et al, 2010; Werner et al, 2011; Zust et al, 2011). …”

Regulation of mRNA capping in the cell cycle

“…5,6 Furthermore, in mammals the first 2 nucleotides are methylated on the O-2 position by CMTR1 and CMTR2. 7,8 O-2 methylation has roles in translation initiation and identifying transcripts as "self" in innate immunity. 4 …”