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 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.
de Murcia
J M
JM
Ecole Supérieure de Biotechnologie de Strasbourg, UPR 9003 du Centre National de la Recherche Scientifique, "Cancérogenèse et Mutagenèse Moléculaire et Structurale", Boulevard Sébastien Brant, F-67400 Illkirch, France.
Niedergang
C
C
Trucco
C
C
Ricoul
M
M
Dutrillaux
B
B
Mark
M
M
Oliver
F J
FJ
Masson
M
M
Dierich
A
A
LeMeur
M
M
Walztinger
C
C
Chambon
P
P
de Murcia
G
G
D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage; D005260:Female; D005347:Fibroblasts; D018390:Gene Targeting; D051379:Mice; D009154:Mutation; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D011247:Pregnancy
D011065:Poly(ADP-ribose) Polymerases