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  • The EMBO Journal (2003) 22, 2255 - 2263
  • doi:10.1093/emboj/cdg206

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

Josiane Ménissier de Murcia1, Michelle Ricoul2, Laurence Tartier1, Claude Niedergang1, Aline Huber1, Françoise Dantzer1, Valérie Schreiber1, Jean-Christophe Amé1, Andrée Dierich3, Marianne LeMeur3, Laure Sabatier2, Pierre Chambon3 and Gilbert de Murcia1

  1. Unité 9003 du CNRS, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, BP 10413, 67412 Illkirch Cedex, France
  2. CEA, Laboratoire de Radiobiologie et Oncologie, 92255 Fontenay-aux Roses, BP 163, 67400 Illkirch Cedex, France
  3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, BP 163, 67400 Illkirch Cedex, France

Correspondence to:

Gilbert de Murcia, E-mail: demurcia@esbs.u-strasbg.fr

Received 21 November 2002; Accepted 6 March 2003; Revised 5 March 2003

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.

  • Keywords:

    • DNA damage,
    • G2/M arrest,
    • mouse development,
    • NAD metabolism,
    • X-chromosome instability