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Molecular and Cellular Biology, December 2008, p. 7380-7393, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.01075-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Rapid Recruitment of BRCA1 to DNA Double-Strand Breaks Is Dependent on Its Association with Ku80{triangledown} ,{dagger}

Leizhen Wei,1 Li Lan,2 Zehui Hong,2 Akira Yasui,2 Chikashi Ishioka,1 and Natsuko Chiba1*

Department of Clinical Oncology,1 Department of Molecular Genetics, Institute of Development, Aging and Cancer (IDAC), Tohoku University, 4-1 Seiryomachi Aoba-ku, Sendai 980-8575, Japan2

Received 9 July 2008/ Returned for modification 29 August 2008/ Accepted 7 October 2008

BRCA1 is the first susceptibility gene to be linked to breast and ovarian cancers. Although mounting evidence has indicated that BRCA1 participates in DNA double-strand break (DSB) repair pathways, its precise mechanism is still unclear. Here, we analyzed the in situ response of BRCA1 at DSBs produced by laser microirradiation. The amino (N)- and carboxyl (C)-terminal fragments of BRCA1 accumulated independently at DSBs with distinct kinetics. The N-terminal BRCA1 fragment accumulated immediately after laser irradiation at DSBs and dissociated rapidly. In contrast, the C-terminal fragment of BRCA1 accumulated more slowly at DSBs but remained at the sites. Interestingly, rapid accumulation of the BRCA1 N terminus, but not the C terminus, at DSBs depended on Ku80, which functions in the nonhomologous end-joining (NHEJ) pathway, independently of BARD1, which binds to the N terminus of BRCA1. Two small regions in the N terminus of BRCA1 independently accumulated at DSBs and interacted with Ku80. Missense mutations found within the N terminus of BRCA1 in cancers significantly changed the kinetics of its accumulation at DSBs. A P142H mutant failed to associate with Ku80 and restore resistance to irradiation in BRCA1-deficient cells. These might provide a molecular basis of the involvement of BRCA1 in the NHEJ pathway of the DSB repair process.

* Corresponding author. Present address: Department of Molecular Immunology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, 4-1 Seiryomachi Aoba-ku, Sendai 980-8575, Japan. Phone: 81-22-717-8478. Fax: 81-22-717-8482. E-mail: nchiba{at}idac.tohoku.ac.jp

{triangledown} Published ahead of print on 20 October 2008.

{dagger} Supplemental material for this paper may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2008, p. 7380-7393, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.01075-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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