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Disruption of Murine Mus81 Increases Genomic Instability and DNA Damage Sensitivity but Does Not Promote Tumorigenesis.
- Source :
- Molecular & Cellular Biology; Sep2005, Vol. 25 Issue 17, p7569-7579, 11p, 1 Diagram, 19 Graphs
- Publication Year :
- 2005
-
Abstract
- 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<superscript>-/-</superscript> 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<superscript>-/-</superscript> 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<superscript>-/-</superscript> mice and cells are hypersensitive to DNA cross-linking agents. Cross-link-induced double-strand break formation is normal in Mus81<superscript>-/-</superscript> cells, but the resolution of repair intermediates is not. The persistence of Rad51 foci in Mus81<superscript>-/-</superscript> cells suggests that Mus81 acts at a late step in the repair of cross-link-induced lesions. Despite these defects, Mus81<superscript>-/-</superscript> mice do not show increased predisposition to lymphoma or any other malignancy in the first year of life. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02707306
- Volume :
- 25
- Issue :
- 17
- Database :
- Complementary Index
- Journal :
- Molecular & Cellular Biology
- Publication Type :
- Academic Journal
- Accession number :
- 18201934
- Full Text :
- https://doi.org/10.1128/MCB.25.17.7569-7579.2005