Reports

Abraxas and RAP80 Form a BRCA1 Protein Complex Required for the DNA Damage Response

Bin Wang,¹ Shuhei Matsuoka,¹ Bryan A. Ballif,^2* Dong Zhang,¹ Agata Smogorzewska,^1,3 Steven P. Gygi,² Stephen J. Elledge¹

The BRCT repeats of the breast and ovarian cancer predisposition protein BRCA1 are essential for tumor suppression. Phosphopeptide affinity proteomic analysis identified a protein, Abraxas, that directly binds the BRCA1 BRCT repeats through a phospho-Ser-X-X-Phe motif. Abraxas binds BRCA1 to the mutual exclusion of BACH1 (BRCA1-associated C-terminal helicase) and CtIP (CtBP-interacting protein), forming a third type of BRCA1 complex. Abraxas recruits the ubiquitin-interacting motif (UIM)–containing protein RAP80 to BRCA1. Both Abraxas and RAP80 were required for DNA damage resistance, G₂-M checkpoint control, and DNA repair. RAP80 was required for optimal accumulation of BRCA1 on damaged DNA (foci) in response to ionizing radiation, and the UIM domains alone were capable of foci formation. The RAP80-Abraxas complex may help recruit BRCA1 to DNA damage sites in part through recognition of ubiquitinated proteins.

¹ Department of Genetics, Center for Genetics and Genomics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
² Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
³ Department of Pathology, Massachusetts General Hospital, Boston, MA 02214, USA.

^* Present address: Department of Biology, University of Vermont, Burlington, VT 05405, USA.

Present address: Genomic Instability Group, Oncology Research, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA.

To whom correspondence should be addressed. E-mail: selledge{at}genetics.med.harvard.edu

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Structural and functional analysis of the Crb2-BRCT2 domain reveals distinct roles in checkpoint signaling and DNA damage repair.

M. L. Kilkenny, A. S. Dore, S. M. Roe, K. Nestoras, J. C.Y. Ho, F. Z. Watts, and L. H. Pearl (2008)
Genes & Dev. 22, 2034-2047
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RAP80 Responds to DNA Damage Induced by Both Ionizing Radiation and UV Irradiation and Is Phosphorylated at Ser205.

J. Yan, X.-P. Yang, Y.-S. Kim, and A. M. Jetten (2008)
Cancer Res. 68, 4269-4276
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Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis.

K. Minter-Dykhouse, I. Ward, M. S.Y. Huen, J. Chen, and Z. Lou (2008)
J. Cell Biol. 181, 727-735
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Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage.

B. Wang and S. J. Elledge (2007)
PNAS 104, 20759-20763
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Launching a ubiquitination cascade at DNA breaks.

X. H. Yang and L. Zou (2007)
PNAS 104, 20645-20646
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Orchestration of the DNA-Damage Response by the RNF8 Ubiquitin Ligase.

N. K. Kolas, J. R. Chapman, S. Nakada, J. Ylanko, R. Chahwan, F. D. Sweeney, S. Panier, M. Mendez, J. Wildenhain, T. M. Thomson, et al. (2007)
Science 318, 1637-1640
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DNA Damage-Dependent Acetylation and Ubiquitination of H2AX Enhances Chromatin Dynamics.

T. Ikura, S. Tashiro, A. Kakino, H. Shima, N. Jacob, R. Amunugama, K. Yoder, S. Izumi, I. Kuraoka, K. Tanaka, et al. (2007)
Mol. Cell. Biol. 27, 7028-7040
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DNA repair capacity of zebrafish.

R. Sussman (2007)
PNAS 104, 13379-13383
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ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage.

S. Matsuoka, B. A. Ballif, A. Smogorzewska, E. R. McDonald III, K. E. Hurov, J. Luo, C. E. Bakalarski, Z. Zhao, N. Solimini, Y. Lerenthal, et al. (2007)
Science 316, 1160-1166
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