Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis.
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.
Dendouga
Najoua
N
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Gao
Hui
H
Moechars
Dieder
D
Janicot
Michel
M
Vialard
Jorge
J
McGowan
Clare H
CH
D000818:Animals; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D004720:Endonucleases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D042822:Genomic Instability / Q000235:genetics*; D051379:Mice; D051135:Rad51 Recombinase; D029701:Saccharomyces cerevisiae Proteins
D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D004720:Endonucleases; C411624:MUS81 protein, S cerevisiae; C498773:Mus81 protein, mouse; D002166:Camptothecin