DNA Damage Regulates Alternative Splicing through Inhibition of RNA Polymerase II Elongation

Manuel J. Muñoz; M. Soledad Pérez Santangelo; Maria P. Paronetto; Manuel de la Mata; Federico Pelisch; Stéphanie Boireau; Kira Glover-Cutter; Claudia Ben-Dov; Matías Blaustein; Juan J. Lozano; Gregory Bird; David Bentley; Edouard Bertrand; Alberto R. Kornblihtt

doi:10.1016/j.cell.2009.03.010

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DNA Damage Regulates Alternative Splicing through Inhibition of RNA Polymerase II Elongation

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DNA Damage Regulates Alternative Splicing through Inhibition of RNA Polymerase II Elongation

Manuel J. Muñoz, M. Soledad Pérez Santangelo, Maria P. Paronetto, Manuel de la Mata, Federico Pelisch, Stéphanie Boireau, Kira Glover-Cutter, Claudia Ben-Dov, Matías Blaustein, Juan J. Lozano, …

Cell, Vol.137(4), pp.708-720

15/05/2009

DOI: https://doi.org/10.1016/j.cell.2009.03.010

PMID: 19450518

Résumé

CELLBIO

DNA

SIGNALING

DNA damage induces apoptosis and many apoptotic genes are regulated via alternative splicing (AS), but little is known about the control mechanisms. Here we show that ultraviolet irradiation (UV) affects cotranscriptional AS in a p53-independent way, through the hyperphosphorylation of RNA polymerase II carboxy-terminal domain (CTD) and a subsequent inhibition of transcriptional elongation, estimated in vivo and in real time. Phosphomimetic CTD mutants not only display lower elongation but also duplicate the UV effect on AS. Consistently, nonphosphorylatable mutants prevent the UV effect. Apoptosis promoted by UV in cells lacking p53 is prevented when the change in AS of the apoptotic gene bcl-x is reverted, confirming the relevance of this mechanism. Splicing-sensitive microarrays revealed a significant overlap of the subsets of genes that have changed AS with UV and those that have reduced expression, suggesting that transcriptional coupling to AS is a key feature of the DNA-damage response.

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Titre: DNA Damage Regulates Alternative Splicing through Inhibition of RNA Polymerase II Elongation
Créateurs - sans rôle: Manuel J. Muñoz - Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, (C1428EHA) Buenos Aires, Argentina
M. Soledad Pérez Santangelo - Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, (C1428EHA) Buenos Aires, Argentina
Maria P. Paronetto - Centre de Regulació Genòmica, Dr. Aiguader 88, 08003 Barcelona, Spain
Manuel de la Mata - Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, (C1428EHA) Buenos Aires, Argentina
Federico Pelisch - Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, (C1428EHA) Buenos Aires, Argentina
Stéphanie Boireau - Institut de Génétique Moléculaire de Montpellier
Kira Glover-Cutter - Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, MS8101, Aurora, CO 80045, USA
Claudia Ben-Dov - Centre de Regulació Genòmica, Dr. Aiguader 88, 08003 Barcelona, Spain
Matías Blaustein - Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, (C1428EHA) Buenos Aires, Argentina
Juan J. Lozano - Centre de Regulació Genòmica, Dr. Aiguader 88, 08003 Barcelona, Spain
Gregory Bird - Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, MS8101, Aurora, CO 80045, USA
David Bentley - Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, MS8101, Aurora, CO 80045, USA
Edouard Bertrand - Institut de Génétique Moléculaire de Montpellier
Alberto R. Kornblihtt - Universidad de Buenos Aires
Détails de publication: Cell, Vol.137(4), pp.708-720
Éditeur: Elsevier Inc
Nombre de pages: 13
Identifiants: 99159298209311
Unité académique: Institut de Génétique Humaine - IGH
Langue: English
Type de ressource: Journal article