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First published online 19 May 2009
doi: 10.1242/jcs.039115

Journal of Cell Science 122, 1990-2002 (2009)
Published by The Company of Biologists 2009
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Research Article

Radiation-induced mitotic catastrophe in PARG-deficient cells

Jean-Christophe Amé1,*, Elise Fouquerel1,*, Laurent R. Gauthier2, Denis Biard3, François D. Boussin2, Françoise Dantzer1, Gilbert de Murcia1 and Valérie Schreiber1,{ddagger}

1 IREBS-FRE3211 du CNRS, Université de Strasbourg, ESBS, Bd Sébastien Brant, BP 10413, 67412 Illkirch Cedex, France
2 Laboratoire de Radiopathologie/INSERM U967, CEA-DSV-IRCM, 92265 Fontenay aux Roses, Cedex 6, France
3 CEA-DSV-IRCM/INSERM U935, Institut A. Lwoff-CNRS, BP 8, 94801 Villejuif cedex, France

{ddagger} Author for correspondence (e-mail: schreiber{at}esbs.u-strasbg.fr)

Accepted 24 February 2009

Poly(ADP-ribosyl)ation is a post-translational modification of proteins involved in the regulation of chromatin structure, DNA metabolism, cell division and cell death. Through the hydrolysis of poly(ADP-ribose) (PAR), Poly(ADP-ribose) glycohydrolase (PARG) has a crucial role in the control of life-and-death balance following DNA insult. Comprehension of PARG function has been hindered by the existence of many PARG isoforms encoded by a single gene and displaying various subcellular localizations. To gain insight into the function of PARG in response to irradiation, we constitutively and stably knocked down expression of PARG isoforms in HeLa cells. PARG depletion leading to PAR accumulation was not deleterious to undamaged cells and was in fact rather beneficial, because it protected cells from spontaneous single-strand breaks and telomeric abnormalities. By contrast, PARG-deficient cells showed increased radiosensitivity, caused by defects in the repair of single- and double-strand breaks and in mitotic spindle checkpoint, leading to alteration of progression of mitosis. Irradiated PARG-deficient cells displayed centrosome amplification leading to mitotic supernumerary spindle poles, and accumulated aberrant mitotic figures, which induced either polyploidy or cell death by mitotic catastrophe. Our results suggest that PARG could be a novel potential therapeutic target for radiotherapy.

Key words: NAD+ metabolism, PARP, DNA repair, Mitosis, Genome stability


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