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Science 316 (5828): 1202-1205

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

Ubiquitin-Binding Protein RAP80 Mediates BRCA1-Dependent DNA Damage Response

Hongtae Kim,1 Junjie Chen,1* Xiaochun Yu2*

Abstract: Mutations in the breast cancer susceptibility gene 1 (BRCA1) are associated with an increased risk of breast and ovarian cancers. BRCA1 participates in the cellular DNA damage response. We report the identification of receptor-associated protein 80 (RAP80) as a BRCA1-interacting protein in humans. RAP80 contains a tandem ubiquitin-interacting motif domain, which is required for its binding with ubiquitin in vitro and its damage-induced foci formation in vivo. Moreover, RAP80 specifically recruits BRCA1 to DNA damage sites and functions with BRCA1 in G2/M checkpoint control. Together, these results suggest the existence of a ubiquitination-dependent signaling pathway involved in the DNA damage response.

1 Department of Therapeutic Radiology, Yale University School of Medicine, Post Office Box 208040, New Haven, CT 06520, USA.
2 Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place, 1520 Biomedical Science Research Building, Ann Arbor, MI 48109, USA.

* To whom correspondence should be addressed. E-mail: Junjie.chen{at}yale.edu (J.C.); xiayu{at}med.umich.edu (X.Y.)

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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L. Feng, J. Huang, and J. Chen (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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Z. Bencokova, M. R. Kaufmann, I. M. Pires, P. S. Lecane, A. J. Giaccia, and E. M. Hammond (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 283, 35173-35185
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Noncanonical E2 Variant-Independent Function of UBC13 in Promoting Checkpoint Protein Assembly.
M. S. Y. Huen, J. Huang, J. Yuan, M. Yamamoto, S. Akira, C. Ashley, W. Xiao, and J. Chen (2008)
Mol. Cell. Biol. 28, 6104-6112
   Abstract »    Full Text »    PDF »
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)
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   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Launching a ubiquitination cascade at DNA breaks.
X. H. Yang and L. Zou (2007)
PNAS 104, 20645-20646
   Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
DNA repair capacity of zebrafish.
R. Sussman (2007)
PNAS 104, 13379-13383
   Abstract »    Full Text »    PDF »
CELL SIGNALING: A Touching Response to Damage.
J. H. J. Petrini (2007)
Science 316, 1138-1139
   Abstract »    Full Text »    PDF »

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