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Science 316 (5828): 1198-1202

Copyright © 2007 by the American Association for the Advancement of Science

RAP80 Targets BRCA1 to Specific Ubiquitin Structures at DNA Damage Sites

Bijan Sobhian,1 Genze Shao,2 Dana R. Lilli,2 Aedín C. Culhane,3 Lisa A. Moreau,4 Bing Xia,1 David M. Livingston,1* Roger A. Greenberg1*{dagger}

Abstract: Mutations affecting the BRCT domains of the breast cancer–associated tumor suppressor BRCA1 disrupt the recruitment of this protein to DNA double-strand breaks (DSBs). The molecular structures at DSBs recognized by BRCA1 are presently unknown. We report the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and the deubiquitinating enzyme (DUB) BRCC36 to MDC1-{gamma}H2AX–dependent lysine6- and lysine63-linked ubiquitin polymers at DSBs. These events are required for cell cycle checkpoint and repair responses to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of DSBs.

1 Dana-Farber Cancer Institute and Department of Genetics and Department of Medicine, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
2 Department of Cancer Biology and Department of Pathology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104–6160, USA.
3 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
4 Department of Radiation Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.

{dagger} Present address: Department of Cancer Biology and Department of Pathology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104–6160, USA.

* To whom correspondence should be addressed. E-mail: david_livingston{at}dfci.harvard.edu (D.M.L.); rogergr{at}mail.med.upenn.edu (R.A.G.)

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