Abstract
Breast cancer-1 (BRCA1) participates in the DNA damage response. However, the mechanism by which BRCA1 is recruited to DNA damage sites remains elusive. Recently, we have demonstrated that a ubiquitin-binding protein, RAP80, is required for DNA damage–induced BRCA1 translocation. Here we identify another component, CCDC98, in the BRCA1–RAP80 complex. CCDC98 mediates BRCA1's association with RAP80. Moreover, CCDC98 controls both DNA damage–induced formation of BRCA1 foci and BRCA1-dependent G2/M checkpoint activation. Together, our results demonstrate that CCDC98 is a BRCA1 binding partner that mediates BRCA1 function in response to DNA damage.
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References
Wu, L.C. et al. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat. Genet. 14, 430–440 (1996).
Lorick, K.L. et al. RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc. Natl. Acad. Sci. USA 96, 11364–11369 (1999).
Brzovic, P.S., Rajagopal, P., Hoyt, D.W., King, M.C. & Klevit, R.E. Structure of a BRCA1-BARD1 heterodimeric RING-RING complex. Nat. Struct. Biol. 8, 833–837 (2001).
Wu-Baer, F., Lagrazon, K., Yuan, W. & Baer, R. The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J. Biol. Chem. 278, 34743–34746 (2003).
Chen, A., Kleiman, F.E., Manley, J.L., Ouchi, T. & Pan, Z.Q. Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase. J. Biol. Chem. 277, 22085–22092 (2002).
Xia, Y., Pao, G.M., Chen, H.W., Verma, I.M. & Hunter, T. Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein. J. Biol. Chem. 278, 5255–5263 (2003).
Yu, X., Chini, C.C., He, M., Mer, G. & Chen, J. The BRCT domain is a phospho-protein binding domain. Science 302, 639–642 (2003).
Rodriguez, M., Yu, X., Chen, J. & Songyang, Z. Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains. J. Biol. Chem. 278, 52914–52918 (2003).
Manke, I.A., Lowery, D.M., Nguyen, A. & Yaffe, M.B. BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302, 636–639 (2003).
Shiozaki, E.N., Gu, L., Yan, N. & Shi, Y. Structure of the BRCT repeats of BRCA1 bound to a BACH1 phosphopeptide: implications for signaling. Mol. Cell 14, 405–412 (2004).
Clapperton, J.A. et al. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat. Struct. Mol. Biol. 11, 512–518 (2004).
Botuyan, M.V. et al. Structural basis of BACH1 phosphopeptide recognition by BRCA1 tandem BRCT domains. Structure 12, 1137–1146 (2004).
Williams, R.S., Lee, M.S., Hau, D.D. & Glover, J.N. Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. Nat. Struct. Mol. Biol. 11, 519–525 (2004).
Venkitaraman, A.R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108, 171–182 (2002).
Scully, R. & Livingston, D.M. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature 408, 429–432 (2000).
Starita, L.M. & Parvin, J.D. The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair. Curr. Opin. Cell Biol. 15, 345–350 (2003).
Narod, S.A. & Foulkes, W.D. BRCA1 and BRCA2: 1994 and beyond. Nat. Rev. Cancer 4, 665–676 (2004).
Yoshida, K. & Miki, Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci. 95, 866–871 (2004).
Ting, N.S. & Lee, W.H. The DNA double-strand break response pathway: becoming more BRCAish than ever. DNA Repair (Amst.) 3, 935–944 (2004).
Sancar, A., Lindsey-Boltz, L.A., Unsal-Kacmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85 (2004).
Zhou, B.B. & Elledge, S.J. The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439 (2000).
Cortez, D., Wang, Y., Qin, J. & Elledge, S.J. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286, 1162–1166 (1999).
Tibbetts, R.S. et al. Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev. 14, 2989–3002 (2000).
Gatei, M. et al. Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Res. 60, 3299–3304 (2000).
Gatei, M. et al. Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies. J. Biol. Chem. 276, 17276–17280 (2001).
Lee, E.Y. BRCA1 and Chk1 in G2/M checkpoint: a new order of regulation. Cell Cycle 1, 178–180 (2002).
Yarden, R.I., Pardo-Reoyo, S., Sgagias, M., Cowan, K.H. & Brody, L.C. BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nat. Genet. 30, 285–289 (2002).
Scully, R. et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90, 425–435 (1997).
Paull, T.T. et al. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr. Biol. 10, 886–895 (2000).
Scully, R. et al. Genetic analysis of BRCA1 function in a defined tumor cell line. Mol. Cell 4, 1093–1099 (1999).
Rogakou, E.P., Boon, C., Redon, C. & Bonner, W.M. Megabase chromatin domains involved in DNA double-strand breaks in vivo. J. Cell Biol. 146, 905–916 (1999).
Cantor, S.B. et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105, 149–160 (2001).
Greenberg, R.A. et al. Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes. Genes Dev. 20, 34–46 (2006).
Yu, X., Fu, S., Lai, M., Baer, R. & Chen, J. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev. 20, 1721–1726 (2006).
Yu, X. & Chen, J. DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains. Mol. Cell. Biol. 24, 9478–9486 (2004).
Yu, X., Wu, L.C., Bowcock, A.M., Aronheim, A. & Baer, R. The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J. Biol. Chem. 273, 25388–25392 (1998).
Wong, A.K. et al. Characterization of a carboxy-terminal BRCA1 interacting protein. Oncogene 17, 2279–2285 (1998).
Li, S. et al. Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage. J. Biol. Chem. 274, 11334–11338 (1999).
Li, S. et al. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406, 210–215 (2000).
Kim, H., Chen, J. & Yu, X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316, 1202–1205 (2007).
Sobhian, B. et al. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316, 1198–1202 (2007).
Wang, B. et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316, 1194–1198 (2007).
Acknowledgements
We thank C. Chen and L. Ye for technical support, and L. Lu for manuscript proofreading. This work was supported by the US Department of Defense Breast Cancer Research Program, the Ovarian Cancer Research Fund and the University of Michigan Cancer Center. X.Y. is the recipient of an American Association for Cancer Research–Susan G. Komen for the Cure Career Development Award for Breast Cancer Research.
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X.Y. purified proteins and identified the BRCA1–CCDC98–RAP80 complex. Z.L. and J.W. analyzed the protein interactions of this complex. Z.L. and X.Y. examined the role of CCDC98 in the formation of DNA damage–induced protein foci and G2/M checkpoint activation. X.Y. drafted the manuscript. All the authors read and approved the final manuscript.
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Liu, Z., Wu, J. & Yu, X. CCDC98 targets BRCA1 to DNA damage sites. Nat Struct Mol Biol 14, 716–720 (2007). https://doi.org/10.1038/nsmb1279
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DOI: https://doi.org/10.1038/nsmb1279
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