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Molecular and Cellular Biology, September 2004, p. 7444-7455, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7444-7455.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

BRCA2 Is Ubiquitinated In Vivo and Interacts with USP11, a Deubiquitinating Enzyme That Exhibits Prosurvival Function in the Cellular Response to DNA Damage

Alan R. Schoenfeld,¹ Sarah Apgar,¹ Georgia Dolios,² Rong Wang,² and Stuart A. Aaronson^1*

Derald H. Ruttenberg Cancer Center,¹ Department of Human Genetics, Mount Sinai School of Medicine, New York, New York²

Received 16 January 2004/ Returned for modification 3 March 2004/ Accepted 3 June 2004

Individuals carrying a germ line mutation of the breast cancer susceptibility gene BRCA2 are predisposed to breast, ovarian, and other types of cancer. The BRCA2 protein has been proposed to function in the repair of DNA double-strand breaks. Using an immunopurification-mass spectrometry approach to identify novel proteins that associate with the BRCA2 gene product, we found that a deubiquitinating enzyme, USP11, formed specific complexes with BRCA2. Moreover, BRCA2 was constitutively ubiquitinated in vivo in the absence of detectable proteasomal degradation. Mitomycin C (MMC) led to decreased BRCA2 protein levels associated with increased ubiquitination, consistent with proteasome-dependent degradation. While BRCA2 could be deubiquitinated by USP11 in transient overexpression assays, a catalytically inactive USP11 mutant had no effect on BRCA2 ubiquitination or protein levels. Antagonism of USP11 function either through expression of this mutant or through RNA interference increased cellular sensitivity to MMC in a BRCA2-dependent manner. All of these results imply that BRCA2 expression levels are regulated by ubiquitination in the cellular response to MMC-induced DNA damage and that USP11 participates in DNA damage repair functions within the BRCA2 pathway independently of BRCA2 deubiquitination.

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* Corresponding author. Mailing address: Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1130, New York, NY 10029. Phone: (212) 659-5400. Fax: (212) 987-2240. E-mail: stuart.aaronson{at}mssm.edu.

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Molecular and Cellular Biology, September 2004, p. 7444-7455, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7444-7455.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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