MYC Mediates mRNA Cap Methylation of Canonical Wnt/β-Catenin Signaling Transcripts By Recruiting CDK7 and RNA Methyltransferase.

MYC is a pleiotropic transcription factor that activates and represses a wide range of target genes and is frequently deregulated in human tumors. While much is known about the role of MYC in transcriptional activation and repression, MYC can also regulate mRNA cap methylation through a mechanism that has remained poorly understood. Here, it is reported that MYC enhances mRNA cap methylation of transcripts globally, specifically increasing mRNA cap methylation of genes involved in Wnt/β-catenin signaling. Elevated mRNA cap methylation of Wnt signaling transcripts in response to MYC leads to augmented translational capacity, elevated protein levels, and enhanced Wnt signaling activity. Mechanistic evidence indicates that MYC promotes recruitment of RNA methyltransferase (RNMT) to Wnt signaling gene promoters by enhancing phosphorylation of serine 5 on the RNA polymerase II carboxy-terminal domain, mediated in part through an interaction between the TIP60 acetyltransferase complex and TFIIH. IMPLICATIONS: MYC enhances mRNA cap methylation above and beyond transcriptional induction. Mol Cancer Res; 15(2); 213-24. ©2016 AACR. ©2016 American Association for Cancer Research.