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Molecular and Cellular Biology, September 2005, p. 7569-7579, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7569-7579.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Disruption of Murine Mus81 Increases Genomic Instability and DNA Damage Sensitivity but Does Not Promote Tumorigenesis

Najoua Dendouga,1,{dagger} Hui Gao,2,{dagger} Dieder Moechars,3 Michel Janicot,1 Jorge Vialard,1 and Clare H. McGowan2,4*

Department of Molecular Biology,2 Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037,4 Oncology Discovery Research and Early Development Europe,1 Functional Genomics Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium3

Received 16 May 2005/ Returned for modification 3 June 2005/ Accepted 15 June 2005

The Mus81-Eme1 endonuclease is implicated in the efficient rescue of broken replication forks in Saccharomyces cerevisiae and Schizosaccharomyces pombe. We have used gene targeting to study the function of the Mus81-Eme1 endonuclease in mammalian cells. Mus81-deficient mice develop normally and are fertile. Surprisingly, embryonic fibroblasts from Mus81–/– animals fail to proliferate in vitro. This proliferation defect can be rescued by expression of the papillomavirus E6 protein that promotes degradation of p53. When grown in culture, Mus81–/– cells have elevated levels of DNA damage, acquire chromosomal aberrations, and are hypersensitive to agents that generate DNA cross-links. In contrast to the situation in yeast, murine Mus81 is not required for replication restart following camptothecin treatment. Mus81–/– mice and cells are hypersensitive to DNA cross-linking agents. Cross-link-induced double-strand break formation is normal in Mus81–/– cells, but the resolution of repair intermediates is not. The persistence of Rad51 foci in Mus81–/– cells suggests that Mus81 acts at a late step in the repair of cross-link-induced lesions. Despite these defects, Mus81–/– mice do not show increased predisposition to lymphoma or any other malignancy in the first year of life.

* Corresponding author. Mailing address: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-2280. Fax: (858) 784-2265. E-mail: chmcg{at}scripps.edu.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, September 2005, p. 7569-7579, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7569-7579.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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