Requirement of Poly (ADP-Ribose) Polymerase in Recovery from DNA Damage in Mice and in Cells

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 γ -irradiation revealed an extreme sensitivity and a high genomic instability to both agents. Following whole body γ -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.