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-ribosyltransf erase, EC 2.4.2.30] is a zinc-finger DNA-binding protein that detects specifically DNA strand breaks generated by genotoxic agents. To deter mine its biological function, me have inactivated both alleles by gene targeting in mice. Treatment of PARP(-/-) mice either by the alkylati ng 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 rapidl y from acute radiation toxicity to the small intestine. Mice-derived P ARP(-/-) cells displayed a high sensitivity to MNU exposure: a G(2)/M arrest in mouse embryonic fibroblasts and a rapid apoptotic response a nd a p53 accumulation were observed in splenocytes. Altogether these r esults demonstrate that PARP is a survival factor playing an essential and positive role during DNA damage recovery.