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J. Biol. Chem., Vol. 280, Issue 15, 14877-14883, April 15, 2005

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Fanconi Anemia Complementation Group D2 (FANCD2) Functions Independently of BRCA2- and RAD51-associated Homologous Recombination in Response to DNA Damage^*

Akihiro Ohashi, Malgorzata Z. Zdzienicka, Junjie Chen¶||, and Fergus J. Couch

From the Department of Laboratory Medicine and Pathology and ^¶Department of Oncology, College of Medicine, Rochester, Minnesota 55905 and Department of Radiation Genetics and Chemical Mutagenesis-Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333AL Leiden, The Netherlands

The BRCA2 breast cancer tumor suppressor is involved in the repair of double strand breaks and broken replication forks by homologous recombination through its interaction with DNA repair protein Rad51. Cells defective in BRCA2·FANCD1 are extremely sensitive to mitomycin C (MMC) similarly to cells deficient in any of the Fanconi anemia (FA) complementation group proteins (FANC). These observations suggest that the FA pathway and the BRCA2 and Rad51 repair pathway may be linked, although a functional connection between these pathways in DNA damage signaling remains to be determined. Here, we systematically investigated the interaction between these pathways. We show that in response to DNA damage, BRCA2-dependent Rad51 nuclear focus formation was normal in the absence of FANCD2 and that FANCD2 nuclear focus formation and mono-ubiquitination appeared normal in BRCA2-deficient cells. We report that the absence of BRCA2 substantially reduced homologous recombination repair of DNA breaks, whereas the absence of FANCD2 had little effect. Furthermore, we established that depletion of BRCA2 or Rad51 had a greater effect on cell survival in response to MMC than depletion of FANCD2 and that depletion of BRCA2 in FANCD2 mutant cells further sensitized these cells to MMC. Our results suggest that FANCD2 mediates double strand DNA break repair independently of Rad51-associated homologous recombination.

Received for publication, December 30, 2004 , and in revised form, January 25, 2005.

^* This work was supported by Grants CA87898 and CA102701 (to F. J. C.) and Grants CA89239 and CA92312 (to J. C.) from the National Institutes of Health and by grants from the Breast Cancer Research Foundation and the Prospect Creek Foundation. 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.

^|| To whom correspondence should be addressed: Dept. of Oncology, Mayo Clinic College of Medicine, 200 First St. S.W., Rochester, MN 55905. Tel.: 507-538-1545; Fax: 507-284-3906; E-mail: Chen.Junjie{at}mayo.edu.

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