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

Priyanka Sharma; Antonios Lioutas; Narcis Fernandez-Fuentes; Javier Quilez; José Carbonell-Caballero; Roni H. G. Wright; Chiara Di Vona; François Le Dily; Roland Schüller; Dirk Eick; Baldomero Oliva

doi:10.1016/j.molcel.2018.10.016

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

Priyanka Sharma, Antonios Lioutas, Narcis Fernandez-Fuentes, Javier Quilez, José Carbonell-Caballero, Roni H. G. Wright, Chiara Di Vona, François Le Dily, Roland Schüller, Dirk Eick, Baldomero Oliva

Department of Life Sciences

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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

Original language	English
Pages (from-to)	84-96.e7
Number of pages	13
Journal	Molecular Cell
Volume	73
Issue number	1
Early online date	21 Nov 2018
DOIs	https://doi.org/10.1016/j.molcel.2018.10.016
Publication status	Published - 03 Jan 2019

Keywords

RNA polymerase II CTD
citrullination
PADI2
arginine 1810
breast cancer cells
proximal promoter pausing
cell proliferation
P_TEFb complex
P-TEFb complex
arginine1810
Protein-Arginine Deiminases/genetics
Cell Proliferation
Humans
Protein-Arginine Deiminase Type 2
Gene Expression Regulation, Neoplastic
Arginine
MCF-7 Cells
Breast Neoplasms/enzymology
Protein Domains
Female
Transcription, Genetic
Citrullination
Promoter Regions, Genetic
Signal Transduction
RNA Polymerase II/chemistry
Gene Expression Regulation, Enzymologic
Positive Transcriptional Elongation Factor B/genetics
Protein Binding
Protein Processing, Post-Translational

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molcel.2018.10.016

Arginine citrullination at the C-terminal domain controls RNA polymerase II transcriptionAccepted author manuscript, 1.05 MBLicence: CC BY-NC-ND

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title = "Arginine Citrullination at the C-Terminal Domain Controls RNA Polymerase II Transcription",

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 = "RNA polymerase II CTD, citrullination, PADI2, arginine 1810, breast cancer cells, proximal promoter pausing, cell proliferation, P_TEFb complex, P-TEFb complex, arginine1810, Protein-Arginine Deiminases/genetics, Cell Proliferation, Humans, Protein-Arginine Deiminase Type 2, Gene Expression Regulation, Neoplastic, Arginine, MCF-7 Cells, Breast Neoplasms/enzymology, Protein Domains, Female, Transcription, Genetic, Citrullination, Promoter Regions, Genetic, Signal Transduction, RNA Polymerase II/chemistry, Gene Expression Regulation, Enzymologic, Positive Transcriptional Elongation Factor B/genetics, Protein Binding, Protein Processing, Post-Translational",

author = "Priyanka Sharma and Antonios Lioutas and Narcis Fernandez-Fuentes and Javier Quilez and Jos{\'e} Carbonell-Caballero and Wright, {Roni H. G.} and {Di Vona}, Chiara and {Le Dily}, Fran{\c c}ois and Roland Sch{\"u}ller and Dirk Eick and Baldomero Oliva",

note = "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 Ju{\'a}n Valc{\'a}rcel, 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 Pin{\'o}s 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 , {\textquoteleft}Centro de Excelencia Severo Ochoa,” and the CERCA Programme/Generalitat de Catalunya . Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2019",

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doi = "10.1016/j.molcel.2018.10.016",

language = "English",

volume = "73",

pages = "84--96.e7",

journal = "Molecular Cell",

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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

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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 -

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

Abstract

Keywords

UN SDGs

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BBSRC Core Strategic Programme in Resilient Crops: Grasslands Gogerddan

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

Abstract

Keywords

UN SDGs

Access to Document

Permanent link

Other files and links

Fingerprint

Projects

BBSRC Core Strategic Programme in Resilient Crops: Grasslands Gogerddan

Cite this