DHX15 regulates CMTR1-dependent gene expression and cell proliferation

Abstract

CMTR1 contributes to mRNA cap formation by methylating the O-2 position of the 1 st 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 1 st nucleotide methylation to a co-transcriptional event. Conversely CMTR1activates 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-CMTR1interaction controls ribosome loading of a subset of mRNAs and impacts on cell proliferation.Key words:CMTR1 / DHX15 / mRNA cap / RNA helicase / gene expression peer-reviewed)

mRNA cap regulation in mammalian cell function and fate

“…These CMTR1 domains may provide a platform by which co-factors and post-translational modifications can mediate regulation of ribose O-2 methylation. The CMTR1 WW domain interacts with Ser-5 phosphorylated C-terminal domain (CTD) of RNA Pol II [ 77 , 78 ]. Since CMTR1 methylates G(5′)ppp(5′)X and m7G(5′)ppp(5′)X equivalently, it is possible that CMTR1 acts prior to RNMT [ 76 , 79 ].…”

“…As described earlier, RNGTT is recruited to Ser-5 phosphorylated RNA Pol II CTD, and the guanylyltransferase activity is stimulated by this interaction [ 61 ]. CMTR1 is also recruited to Ser-5 phospho-CTD and RNMT is recruited to RNA pol II, probably indirectly, in a phospho-CTD-dependent manner [ 69 , 77 , 78 ]. Currently, there is no evidence that RNMT and CMTR1 are activated by interaction with the RNA pol II CTD.…”

Interactome analysis of the human Cap‐specific mRNA (nucleoside‐2′‐O‐)‐methyltransferase 1 (hMTr1) protein

“…We also showed that hMTr1 interacts with RNA in vitro and with the C-terminal domain of the alpha subunit of RNA polymerase II using a yeast two-hybrid system. 8 Synthesis of mRNA requires the participation of a large set of proteins and ribonucleoprotein complexes that act cotranscriptionally to catalyze synthesis of the 5′-end cap, excision of introns, and polyadenylation of the 3′ terminus. Although the crystal structure described for hMTr1 6 revealed important details on the mechanism of action of this methyltransferase regarding its catalytic activity, there is scarce information about the interactions of hMTr1 with components of the RNA synthesis machinery.…”

Dissection of the molecular targets and signaling pathways of Guzhi Zengsheng Zhitongwan based on the analysis of serum proteomics

“…However, there is still no obvious evidence regarding their roles in regulating cartilage growth and development. DHX15 is a DEAH-box helicase involved in RNA processing, splicing, and ribosome biogenesis, which impacts gene expression and cell proliferation [62]. PKM is an enzyme responsible for the conversion of pyruvate and ATP in glycolysis, and plays a key role in regulating cell metabolism and proliferation [63].…”