DHX15 regulates CMTR1-dependent gene expression and cell proliferation

Abstract

CMTR1 contributes to mRNA cap formation by methylating the O-2 position of the 1st transcribed nucleotide ribose. mRNA cap O-2 methylation has roles in mRNA translation and self-RNA tolerance in innate immunity, however its role in cell physiology is unclear. We report that CMTR1 is recruited to Serine-5 phosphorylated RNA Pol II CTD, facilitating cotranscriptional methylation. We isolated CMTR1 in a complex with DHX15, an RNA helicase functioning in splicing and ribosome biogenesis, and characterised it as a regulator of CMTR1. When bound to DHX15, CMTR1 activity is repressed and prevented from binding to RNA pol II, thus constraining 1st nucleotide methylation to a co-transcriptional event. Conversely CMTR1 activates DHX15 helicase activity and influences its nuclear localisation, which is likely to impact on several nuclear functions. The impact of the CMTR1-DHX15 interaction is complex and will depend on the relative expression of these enzymes and their interactors, and the cellular dependency on different RNA processing pathways. In HCC1806 cells, the DHX15-CMTR1 interaction controls ribosome loading of a subset of mRNAs and impacts on cell proliferation.