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Research Article |
1 Max Planck Institute of Molecular Genetics, 14195 Berlin, Germany
2 Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94040, USA
3 Soochow University, Suzhou 215007, P.R. China
4 Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA
5 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA
6 Institute of Radiation Biology, GSF, National Research Center for Environment and Health, 85758 Neuherberg, Germany
Author for correspondence (e-mail: haaf{at}humgen.klinik.uni-mainz.de)
Accepted October 4, 2001
After exposure of mammalian cells to DNA damage, the endogenous Rad51 recombination protein is concentrated in multiple discrete foci, which are thought to represent nuclear domains for recombinational DNA repair. Overexpressed Rad51 protein forms foci and higher-order nuclear structures, even in the absence of DNA damage, in cells that do not undergo DNA replication synthesis. This correlates with increased expression of the cyclin-dependent kinase (Cdk) inhibitor p21. Following DNA damage, constitutively Rad51-overexpressing cells show reduced numbers of DNA breaks and chromatid-type chromosome aberrations and a greater resistance to apoptosis. In contrast, Rad51 antisense inhibition reduces p21 protein levels and sensitizes cells to etoposide treatment. Downregulation of p21 inhibits Rad51 foci formation in both normal and Rad51-overexpressing cells. Collectively, our results show that Rad51 expression, Rad51 foci formation and p21 expression are interrelated, suggesting a functional link between mammalian Rad51 protein and p21-mediated cell cycle regulation. This mechanism may contribute to a highly effective recombinational DNA repair in cell cycle-arrested cells and protection against DNA damage-induced apoptosis.
Key words: Apoptosis, Cell cycle arrest, DNA repair, p21, Rad51
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