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Mol Cell. 2018 Nov 6. pii: S1097-2765(18)30848-7. doi: 10.1016/j.molcel.2018.10.016. [Epub ahead of print]

Arginine Citrullination at the C-Terminal Domain Controls RNA Polymerase II Transcription.

Author information

1
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona 08003, Spain.
2
IBERS, Institute of Biological, Environmental and Rural Science, Aberystwyth University, Aberystwyth SY23 3EB, UK.
3
Department of Molecular Epigenetics, Helmholtz Center Munich, Center of Integrated Protein Science, Munich, Germany.
4
Universitat Pompeu Fabra (UPF), Barcelona, Spain; Structural Bioinformatics Laboratory (GRIB-IMIM), Department of Experimental and Health Sciences, Barcelona 08003, Spain.
5
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain. Electronic address: miguel.beato@crg.eu.

Abstract

The post-translational modification of key residues at the C-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 results 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.

KEYWORDS:

P-TEFb complex; PADI2; RNA polymerase II CTD; arginine1810; breast cancer cells; cell proliferation; citrullination; proximal promoter pausing

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