Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse.
The DNA damage-dependent poly(ADP-ribose) polymerases, PARP-1 and PARP-2, homo- and heterodimerize and are both involved in the base excision repair (BER) pathway. Here, we report that mice carrying a targeted disruption of the PARP-2 gene are sensitive to ionizing radiation. Following alkylating agent treatment, parp-2(-/-)-derived mouse embryonic fibroblasts exhibit increased post-replicative genomic instability, G(2)/M accumulation and chromosome mis-segregation accompanying kinetochore defects. Moreover, parp-1(-/-)parp-2(-/-) double mutant mice are not viable and die at the onset of gastrulation, demonstrating that the expression of both PARP-1 and PARP-2 and/or DNA-dependent poly(ADP-ribosyl) ation is essential during early embryogenesis. Interestingly, specific female embryonic lethality is observed in parp-1(+/-)parp-2(-/-) mutants at E9.5. Meta phase analyses of E8.5 embryonic fibroblasts highlight a specific instability of the X chromosome in those females, but not in males. Together, these results support the notion that PARP-1 and PARP-2 possess both overlapping and non-redundant functions in the maintenance of genomic stability.
Ménissier de Murcia
Josiane
J
Unité 9003 du CNRS, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, BP 10413, 67412 Illkirch Cedex, France.
Ricoul
Michelle
M
Tartier
Laurence
L
Niedergang
Claude
C
Huber
Aline
A
Dantzer
Françoise
F
Schreiber
Valérie
V
Amé
Jean-Christophe
JC
Dierich
Andrée
A
LeMeur
Marianne
M
Sabatier
Laure
L
Chambon
Pierre
P
de Murcia
Gilbert
G
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002875:Chromosomes; D004249:DNA Damage; D017931:DNA Primers; D005314:Embryonic and Fetal Development / Q000502:physiology*; D005804:Genes, Lethal; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D011836:Radiation Tolerance
D017931:DNA Primers; D007527:Isoenzymes; D008770:Methylnitrosourea; D011065:Poly(ADP-ribose) Polymerases