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Molecular and Cellular Biology, March 2001, p. 1828-1832, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1828-1832.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Early Embryonic Lethality in PARP-1 Atm Double-Mutant Mice Suggests a Functional Synergy in Cell Proliferation during Development

Josiane Ménissier-de Murcia,1,* Manuel Mark,2 Olivia Wendling,2 Anthony Wynshaw-Boris,3 and Gilbert de Murcia1

Ecole Supérieure de Biotechnologie de Strasbourg, UPR 9003 du CNRS, Cancérogenèse et Mutagenèse Moléculaire et Structurale,1 and Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France,2 67400 Illkirch Cedex, France, and Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 208923

Received 7 November 2000/Accepted 10 November 2000

PARP-1 and ATM are both involved in the response to DNA strand breaks, resulting in induction of a signaling network responsible for DNA surveillance, cellular recovery, and cell survival. ATM interacts with double-strand break repair pathways and induces signals resulting in the control of the cell cycle-coupled checkpoints. PARP-1 acts as a DNA break sensor in the base excision repair pathway of DNA. Mice with mutations inactivating either protein show radiosensitivity and high radiation-induced chromosomal aberration frequencies. Embryos carrying double mutations of both PARP-1 and Atm genes were generated. These mutant embryos show apoptosis in the embryo but not in extraembryonic tissues and die at embryonic day 8.0, although extraembryonic tissues appear normal for up to 10.5 days of gestation. These results reveal a functional synergy between PARP-1 and ATM during a period of embryogenesis when cell cycle checkpoints are not active and the embryo is particularly sensitive to DNA damage. These results suggest that ATM and PARP-1 have synergistic phenotypes due to the effects of these proteins on signaling DNA damage and/or on distinct pathways of DNA repair.

* Corresponding author. Mailing address: UPR 9003 du CNRS, Laboratoire conventionné avec le Commissariat à l'Energie Atomique, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400 Illkirch, France. Phone: (33) 388 65 53 64. Fax: (33) 388 65 53 52. E-mail: josiane{at}esbs.u-strasbg.fr.

Molecular and Cellular Biology, March 2001, p. 1828-1832, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1828-1832.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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