Deimination of arginine at the C-terminal domain favors RNA polymerase II pause release

Abstract

HighlightsO_LIPeptidyl arginine deiminase 2 (PADI2) citrullinates arginine1810 (cit1810) present at carboxy-terminal domain of RNA polymerase II (RNAP2-CTD).\nC_LIO_LIPADI2 and R1810 of RNAP2-CTD regulate transcription and proliferation of breast cancer cells.\nC_LIO_LIAbsence of cit1810 at RNAP2-CTD leads to RNAP2 accumulation at proximal promoter regions.\nC_LIO_LICit1810 at RNAP2-CTD facilitate interaction with P-TFEb complex.\nC_LI\n\nSUMMARYThe post-translational modification of key residues at the carboxy-terminal domain of RNA polymerase II (RNAP2-CTD), coordinates transcription, splicing, and RNA processing by modulating its capacity to act as a landing platform for a variety of protein complexes. Here, we identify a new modification at the CTD, the deimination of arginine and its conversion to citrulline by peptidyl arginine deiminase 2 (PADI2), an enzyme that has been associated with several diseases including cancer. We show that among PADI family members, only PADI2 citrullinates R1810 (Cit1810) at repeat 31 of the CTD. Depletion of PADI2 or loss of R1810 result in accumulation of RNAP2 at transcription start sites, reduced gene expression and inhibition of cell proliferation. Cit1810 is needed for interaction with the P-TEFb (positive transcription elongation factor b) kinase complex and for its recruitment to chromatin. In this way, CTD-Cit1810 favors RNAP2 pause release and efficient transcription in breast cancer cells.