TY - JOUR
T1 - Arginine Citrullination at the C-Terminal Domain Controls RNA Polymerase II Transcription
AU - Sharma, Priyanka
AU - Lioutas, Antonios
AU - Fernandez-Fuentes, Narcis
AU - Quilez, Javier
AU - Carbonell-Caballero, José
AU - Wright, Roni H. G.
AU - Di Vona, Chiara
AU - Le Dily, François
AU - Schüller, Roland
AU - Eick, Dirk
AU - Oliva, Baldomero
N1 - Funding Information:
We thank David Bentley for GST-CTD plasmids and Hiroshi Kimura for RNAP2 S2P/5P monoclonal antibodies. We thank CRG Genomics, Protein Technology, and the Advanced Light Microscopy facilities for all technical support. We are grateful to all the members of the chromatin and gene expression lab for useful suggestions. We acknowledge Juán Valcárcel, Guillermo P. Vicent, Enrique Vidal Ocabo, and Gwendal Dujardin from CRG for constructive criticism and advice during the course of this work. P.S. was supported by a Novartis fellowship and Beatriu de Pinós fellowship (co-founded by Marie Curie Action , 2013 BP_B 00061 ). Our work was supported by Spanish MEC ( SAF2016-75006 ), the Catalan Government ( 2017-2019 SGR 747_MBeato ), and the European Research Council Synergy Grant “4DGenome” ( 609989 ). We acknowledge the support of the Spanish Ministry of Economy and Competitiveness , ‘Centro de Excelencia Severo Ochoa,” and the CERCA Programme/Generalitat de Catalunya .
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2019/1/3
Y1 - 2019/1/3
N2 - 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
AB - 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
KW - RNA polymerase II CTD
KW - citrullination
KW - PADI2
KW - arginine 1810
KW - breast cancer cells
KW - proximal promoter pausing
KW - cell proliferation
KW - P_TEFb complex
KW - P-TEFb complex
KW - arginine1810
KW - Protein-Arginine Deiminases/genetics
KW - Cell Proliferation
KW - Humans
KW - Protein-Arginine Deiminase Type 2
KW - Gene Expression Regulation, Neoplastic
KW - Arginine
KW - MCF-7 Cells
KW - Breast Neoplasms/enzymology
KW - Protein Domains
KW - Female
KW - Transcription, Genetic
KW - Citrullination
KW - Promoter Regions, Genetic
KW - Signal Transduction
KW - RNA Polymerase II/chemistry
KW - Gene Expression Regulation, Enzymologic
KW - Positive Transcriptional Elongation Factor B/genetics
KW - Protein Binding
KW - Protein Processing, Post-Translational
UR - http://www.scopus.com/inward/record.url?scp=85059194541&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2018.10.016
DO - 10.1016/j.molcel.2018.10.016
M3 - Article
C2 - 30472187
SN - 1097-2765
VL - 73
SP - 84-96.e7
JO - Molecular Cell
JF - Molecular Cell
IS - 1
ER -