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J. Biol. Chem., Vol. 281, Issue 30, 21312-21320, July 28, 2006

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Functional Interplay between BRCA2/FancD1 and FancC in DNA Repair^*

From the Department of Immunology and Molecular Genetics, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan

A rare hereditary disorder, Fanconi anemia (FA), is caused by mutations in an array of genes, which interact in a common FA pathway/network. These genes encode components of the FA "core" complex, a key factor FancD2, the familial breast cancer suppressor BRCA2/FancD1, and Brip1/FancJ helicase. Although BRCA2 is known to play a pivotal role in homologous recombination repair by regulating Rad51 recombinase, the precise functional relationship between BRCA2 and the other FA genes is unclear. Here we show that BRCA2-dependent chromatin loading of Rad51 after mitomycin C treatment was not compromised by disruption of FANCC or FANCD2. Rad51 and FancD2 form colocalizing subnuclear foci independently of each other. Furthermore, we created a conditional BRCA2 truncating mutation lacking the C-terminal conserved domain (CTD) (brca2CTD), and disrupted the FANCC gene in this background. The fancc/brca2CTD double mutant revealed an epistatic relationship between FANCC and BRCA2 CTD in terms of x-ray sensitivity. In contrast, levels of cisplatin sensitivity and mitomycin C-induced chromosomal aberrations were increased in fancc/brca2CTD cells relative to either single mutant. Taken together, these results indicate that FA proteins work together with BRCA2/Rad51-mediated homologous recombination in double strand break repair, whereas the FA pathway plays a role that is independent of the CTD of BRCA2 in interstrand cross-link repair. These results provide insights into the functional interplay between the classical FA pathway and BRCA2.

Received for publication, April 6, 2006 , and in revised form, May 9, 2006.

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (to H. K. and M. T.) and the Ministry of Health, Labor, and Welfare, Japan (to M. T.). Financial support was also provided by the Naito Foundation (to M. T.), the Sagawa Foundation for Promotion of Cancer Research (to M. T.), and Project Research Grant 17-103N from the Kawasaki Medical School (to H. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Currrent address: Pediatric Hematology/Oncology and Stem Cell Transplantation, Schneider Children's Hospital, New Hyde Park, NY 11040.

² To whom correspondence should be addressed. Tel.: 81-86-462-1111; Fax: 81-86-464-1187; E-mail: mtakata{at}med.kawasaki-m.ac.jp.

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