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Nucleic Acids Research 2006 34(5):1358-1368; doi:10.1093/nar/gkl020
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Published online 6 March 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Article

Repression of mutagenesis by Rad51D-mediated homologous recombination

John M. Hinz, Robert S. Tebbs, Paul F. Wilson1, Peter B. Nham, Edmund P. Salazar, Hatsumi Nagasawa1, Salustra S. Urbin, Joel S. Bedford1 and Larry H. Thompson*

Biosciences Directorate, Lawrence Livermore National Laboratory Livermore, CA 94551, USA 1Department of Environmental and Radiological Health Sciences Colorado State University Fort Collins, CO 80523, USA

*To whom correspondence should be addressed. Tel: +1 925 422 5658; Fax: +1 925 422 2099; Email: thompson14{at}llnl.gov

Received December 20, 2005. Revised February 14, 2006. Accepted February 14, 2006.

Homologous recombinational repair (HRR) restores chromatid breaks arising during DNA replication and prevents chromosomal rearrangements that can occur from the misrepair of such breaks. In vertebrates, five Rad51 paralogs are identified that contribute in a nonessential but critical manner to HRR proficiency. We constructed and characterized a knockout of the paralog Rad51D in widely studied CHO cells. The rad51d mutant (clone 51D1) displays sensitivity to a diverse spectrum of induced DNA damage including {gamma}-rays, ultraviolet (UV)-C radiation, and methyl methanesulfonate (MMS), indicating the broad relevance of HRR to genotoxicity. Spontaneous chromatid breaks/gaps and isochromatid breaks are elevated 3- to 12-fold, but the chromosome number distribution remains unchanged. Most importantly, 51D1 cells exhibit a 12-fold-increased rate of hprt mutation, as well as 4- to 10-fold increased rates of gene amplification at the dhfr and CAD loci, respectively. Xrcc3 irs1SF cells from the same parental CHO line show similarly elevated mutagenesis at these three loci. Collectively, these results confirm the a priori expectation that HRR acts in an error-free manner to repress three classes of genetic alterations (chromosomal aberrations, loss of gene function and increased gene expression), all of which are associated with carcinogenesis.


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