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Science 25 May 2007:
Vol. 316. no. 5828, pp. 1198 - 1202
DOI: 10.1126/science.1139516
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Reports

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}

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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