DNA damage is often a key event in triggering malignancy (see the Perspective by Petrini). Much of the cellular response to DNA damage is mediated by two protein kinases, ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related kinase). Matsuoka et al. report a proteomic screen that implicates more than 700 proteins in the cellular response to DNA damage caused by ionizing radiation. Antibodies that recognized the phosphorylated forms of peptides containing consensus phosphorylation sites recognized by ATM or ATR were used to search for previously unrecognized substrates. These results provide a resource for identification of previously unrecognized proteins that function in control of DNA damage in mammalian cells. Three reports, Wang et al., Sobhian et al., and Kim et al., describe a complex of proteins that interact with the breast cancer-associated tumor suppressor gene product BRCA1 and implicate covalent modification of proteins by ubiquitination in regulating the functions of BRCA1 and its partners in the cellular response to DNA damage. A complex of BRCA1 with the protein Bard1 is known to have ubiquitin ligase activity. In the present work, BRCA1 formed a complex at sites of DNA damage with RAP80, a protein with a ubiquitin-interacting motif domain, and RAP80 contributed to localization of BRCA1 to sites of DNA damage. A third protein, Abraxas, appears to mediate interaction of BRCA1 with Rap80. BRCA1 complexes also contained BRCC36, a deubiquitinating enzyme. The DNA damage checkpoint that halts division of cells with damaged DNA was defective in cells lacking RAP80. Thus, the BRCA1-Abraxas-RAP80 complex appears to target BRCA1 to sites of DNA damage.
S. Matsuoka, B. B. Ballif, A. Smogorzewska, E. R. McDonald, III, K. E. Hurov, J. Luo, C. E. Bakalarski, Z. Zhao, N. Solimini, Y. Lerenthal, Y. Shiloh, S. P. Gygi, S. J. Elledge, ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160-1166 (2007). [Abstract] [Full Text]
B. Wang, S. Matsuoka, B. A. Ballif, D. Zhang, A. Smogorzewska, S. P. Gygi, S. J. Elledge, Abraxs and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316, 1194-1198 (2007). [Abstract] [Full Text]
B. Sobhian, G. Shao, D. R. Lilli, A. C. Culhane, L. A. Moreau, B. Xia, D. M. Livingston, R. A. Greenberg, RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316, 1198-1202 (2007). [Abstract] [Full Text]