Abstract

PARP-1 and PARP-2 are until now the sole members of the PARP family whose catalytic activity is stimulated by DNA strand-breaks suggesting that they are both involved in the cellular response to DNA damage [1]. Like PARP-1–/– mice, PARP-2–/– mice are also sensitive to ionizing radiation and display genomic instability [2]. The deficiency in either PARP-1 [3–5] or PARP-2 [6] slows down the BER process. PARP-1–/–, PARP-2–/– double mutants are not viable and die around E7.5, a developmental stage when embryonic cells are hypersensitive to DNA-damage [7]. The demise during this developmental window is known to occur in embryos lacking BER factors (XRCC1 or APE), factors involved in double strand breaks repair (rad 50, rad 51) and Atr. Thus, PARP-1 and PARP-2 have complementary functions that are essential for development. Specific female embryonic lethality was observed in PARP-1+/–, PARP-2–/– mutant embryos at E9.5. Metaphase analyses at E8.5 highlight a specific instability of X-chromosomes in those females but not in males. X-chromosome missegregation and aneuploidy are the most frequent events suggesting a kinetochore defect that may lead to a mitotic catastrophe and developmental arrest around E9.5. Similar female-specific lethality was reported associated with mutations in DNA repair genes [8,9]. In these cases, even if a critical level of DNA repair capacity is reached, avoiding a complete early lethality, the poor DNA repair efficiency may lead to a severe genomic instability, detrimental first for the females. References: 1.Amé et al: J Biol Chem, 1999; 274: 17860-17868 2.Ménissier-de Murcia J et al: submitted 3.Beneke et al: Mol Cel Biol, 2000; 20: 6695-6703 4.Dantzer et al: Biochemistry, 2000; 39: 7559-7569 5.Masutani et al: Mutat Res, 2000; 406: 156-166 6.Schreiber et al: J Biol Chem, 2002; 277: 23028-23036 7.Heyer et al: Genes Dev, 2000; 14: 2072-2084 8.Cranston et al: Nat Genet, 1997; 17: 114-118 9.Healey et al: Nat Genet, 2000; 26: 362-364

Keywords: KO mice, NAD metabolism, BER, X-chromosome, genomic instability