Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse

• Published in: The EMBO journal Vol. 22; no. 9; pp. 2255 - 2263
• Main Authors: de Murcia, Gilbert, Ménissier de Murcia, Josiane, Ricoul, Michelle, Tartier, Laurence, Niedergang, Claude, Huber, Aline, Dantzer, Françoise, Schreiber, Valérie, Amé, Jean-Christophe, Dierich, Andrée, LeMeur, Marianne, Sabatier, Laure, Chambon, Pierre
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.05.2003; Blackwell Publishing Ltd; EMBO Press; Oxford University Press
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Base Sequence; Biochemistry, Molecular Biology; Chromosomes; DNA Damage; DNA Primers; Embryonic and Fetal Development; Embryonic and Fetal Development - physiology; G2/M arrest; Genes, Lethal; Isoenzymes; Isoenzymes - genetics; Isoenzymes - physiology; Life Sciences; Methylnitrosourea; Methylnitrosourea - pharmacology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; mouse development; NAD metabolism; Poly(ADP-ribose) Polymerases; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - physiology; Radiation Tolerance; X-chromosome instability
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/cdg206

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, G2/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.