A new insight into MYC action: control of RNA polymerase II methylation and transcription termination

Abstract

AbstractA common catastrophic event in most human cancers is deregulation of MYC, a multifunctional transcription factor that controls gene expression in partnership with MAX and drives key biological mechanisms of the cell. Restraining its activity impairs cancer cell features and prevents tumor development, as shown by Omomyc - a 90 amino acid mini-protein interfering with MYC activity. MYC regulates many aspects of transcription by RNA polymerase II (RNAPII), such as activation, pause release, and elongation. That it may have a role in transcription termination as well is suggested by our finding of an interaction between MYC and the Protein Arginine Methyltransferase 5 (PRMT5), which catalyzes symmetrical dimethylation of RNAPII at the arginine residue R1810 (R1810me2s) allowing proper termination and splicing of transcripts. Here we show that MYC overexpression strongly increases R1810me2s, while the concomitant expression of Omomyc or a MYC-specific shRNA counteracts this capacity. Omomyc impairs as well Serine 2 phosphorylation in the RNAPII carboxyterminal domain, a modification that sustains transcript elongation and is enhanced by MYC. By displacing MYC on DNA, Omomyc reshapes RNAPII distribution along genes, leading to greater occupancy of promoter and termination sites. It is unclear how this may affect expression of the variety of genes that control metabolic, biosynthetic, and other pathways and are up or down regulated upon MYC inhibition. Genes belonging to a signature of direct MYC targets are instead strongly downregulated following MYC inhibition, with a weak correlation with RNAPII occupancy at promoters. Our data point to a MYC/ PRMT5/RNAPII axis that controls termination via RNAPII dimethylation (R1810me2s) and may contribute to fine-tune the expression of genes altered by MYC overexpression in cancer cells. It remains to be seen which role this may have in tumor development and maintenance.