Wang, BinElledge, Stephen J.2019-10-122007Wang, B., and S. J. Elledge. 2007. “Ubc13/Rnf8 Ubiquitin Ligases Control Foci Formation of the Rap80/Abraxas/Brca1/Brcc36 Complex in Response to DNA Damage.” Proceedings of the National Academy of Sciences104 (52): 20759–63. doi:10.1073/pnas.0710061104.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41542702The Brca1 A complex contains Brca1/Bard1, Abraxas, Rap80, and Brcc36; however, with the exception of the Brca1-Abraxas interaction, how the A complex is assembled is not known. The A complex is localized to sites of DNA damage through the UIM domains of RAP80, which bind K63-linked polyubiquitin chains. In this study, we identified an FHA domain RING finger E3 ubiquitin ligase, RNF8, and an E2-conjugating enzyme known to form K63-polyubiquitin chains, Ubc13, each of which is required to recruit the Brca1 A complex to sites of DNA damage. Rnf8 localizes to sites of DNA damage through an FHA-domain-containing region. We found that Rap80 contains an Abraxas interaction domain [AIR (Abraxas-interacting region)] required for association of Rap80 with Abraxas, Brca1, and Brcc36. Abraxas and Brcc36 associate through coiled-coil domains on each protein. These data suggest a model through which Ubc13 and Rnf8 are recruited to sites of DNA damage through DNA-damage-induced phosphorylation of a chromatin-associated protein and generate polyubiquitin chains that then recruit Rap80 and the entire Brca1 A complex to DNA-damage foci. This sequential E3 ubiquitin ligase recruitment constitutes a ubiquitin ligase cascade required for DNA repair and checkpoint signaling.en-USJournal Article2019-10-1210.1073/pnas.0710061104