Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells

Josiane Ménissier de Murcia(Centre National pour la Recherche Scientifique et Technique (CNRST)), C. Niedergang(Centre National pour la Recherche Scientifique et Technique (CNRST)), Carlotta Trucco(Centre National pour la Recherche Scientifique et Technique (CNRST)), Michèle Ricoul(Centre National pour la Recherche Scientifique et Technique (CNRST)), Bernard Dutrillaux(Institut de Biologie et de Chimie des Protéines), Manuel Mark(Centre National pour la Recherche Scientifique et Technique (CNRST)), F. Javier Oliver(Centre National pour la Recherche Scientifique et Technique (CNRST)), Murielle Masson(Centre National pour la Recherche Scientifique et Technique (CNRST)), A. Dierich(Centre National pour la Recherche Scientifique et Technique (CNRST)), Marianne LeMeur(Centre National pour la Recherche Scientifique et Technique (CNRST)), C Walztinger(Centre National pour la Recherche Scientifique et Technique (CNRST)), Pierre Chambon(Centre National pour la Recherche Scientifique et Technique (CNRST)), Gilbert de Murcia(Centre National pour la Recherche Scientifique et Technique (CNRST))
Proceedings of the National Academy of Sciences
July 8, 1997
10.1073/pnas.94.14.7303
Cited by 1,053Open Access
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Abstract

Poly(ADP-ribose) polymerase [PARP; NAD+ ADP-ribosyltransferase; NAD+: poly(adenosine-diphosphate-D-ribosyl)-acceptor ADP-D-ribosyltransferase, EC 2.4.2.30] is a zinc-finger DNA-binding protein that detects specifically DNA strand breaks generated by genotoxic agents. To determine its biological function, we have inactivated both alleles by gene targeting in mice. Treatment of PARP-/- mice either by the alkylating agent N-methyl-N-nitrosourea (MNU) or by gamma-irradiation revealed an extreme sensitivity and a high genomic instability to both agents. Following whole body gamma-irradiation (8 Gy) mutant mice died rapidly from acute radiation toxicity to the small intestine. Mice-derived PARP-/- cells displayed a high sensitivity to MNU exposure: a G2/M arrest in mouse embryonic fibroblasts and a rapid apoptotic response and a p53 accumulation were observed in splenocytes. Altogether these results demonstrate that PARP is a survival factor playing an essential and positive role during DNA damage recovery.

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