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Ataxia Telangiectasia Mutated and Checkpoint Kinase 2 Regulate BRCA1 to Promote the Fidelity of DNA End-Joining

¹ Graduate Institute of Life Sciences, National Defense Medical Center; ² Institute of Biomedical Sciences and ³ Life Science Library, Academia Sinica; and ⁴ Institute of Public Health, National Yang-Ming University, Taipei, Taiwan

Requests for reprints: Chen-Yang Shen, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan. Phone: 886-2-2789-9036; Fax: 886-2-2782-3047; E-mail: bmcys{at}ibms.sinica.edu.tw.

Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are the two mechanisms responsible for repairing DNA double-strand breaks (DSBs) and act in either a collaborative or competitive manner in mammalian cells. DSB repaired by NHEJ may be more complicated than the simple joining of the ends of DSB, because, if nucleotides were lost, it would result in error-prone repair. This has led to the proposal that a subpathway of precise NHEJ exists that can repair DSBs with higher fidelity; this is supported by recent findings that the expression of the HR gene, BRCA1, is causally linked to in vitro and in vivo precise NHEJ activity. To further delineate this mechanism, the present study explored the connection between NHEJ and the cell-cycle checkpoint proteins, ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (Chk2), known to be involved in activating BRCA1, and tested the hypothesis that ATM and Chk2 promote precise end-joining by BRCA1. Support for this hypothesis came from the observations that (a) knockdown of ATM and Chk2 expression affected end-joining activity; (b) in BRCA1-defective cells, precise end-joining activity was not restored by a BRCA1 mutant lacking the site phosphorylated by Chk2 but was restored by wild-type BRCA1 or a mutant mimicking phosphorylation by Chk2; (c) Chk2 mutants lacking kinase activity or with a mutation at a site phosphorylated by ATM had a dominant negative effect on precise end-joining in BRCA1-expressing cells. These results suggest that the other two HR regulatory proteins, ATM and Chk2, act jointly to regulate the activity of BRCA1 in controlling the fidelity of DNA end-joining by precise NHEJ. (Cancer Res 2006; 66(3): 1391-400)

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