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

J M De Murcia (1) , C Niedergang , C Trucco , M Ricoul , B Dutrillaux (2) , M Mark (3) , F J Oliver , M Masson (1) , A Dierich , M Lemeur , C Walztinger , P Chambon , G De Murcia (1)

1 BSC - Biotechnologie et signalisation cellulaire
2 IBCP - Institut de biologie et chimie des protéines [Lyon]
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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.

Domaines: Biochimie, Biologie Moléculaire; Biologie structurale [q-bio.BM]

J M De Murcia, C Niedergang, C Trucco, M Ricoul, B Dutrillaux, et al.. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proceedings of the National Academy of Sciences of the United States of America, 1997, 94 (14), pp.7303-7. ⟨10.1073/pnas.94.14.7303⟩. ⟨hal-02371495⟩