Figure 2

Models for ubiquitin accumulation at DSB. Upon DSBs, γH2AX could be monoubiquitinated (a) so that RNF8-Ubc13-Mms2 can attach additional Lys63-linked polyubiquitin chains on the ubiquitin (b). The E2 and E3 for monoubiquitination are unknown. BRCA1-BARD1 is then targeted to the polyubiquitin chains through RAP80-ABRA1 in a manner dependent on ABRA1 phosphorylation. BRCA1-BARD1 interacts with UbcH5c and mediates further polyubiquitin chains, including Lys6-linked chains (c). The BRCA1-BARD1-induced polyubiquitin chains further recruit additional BRCA1-BARD1 complexes to damaged sites, resulting in focal accumulation of polyubiquitin chains (d). The polyubiquitin chain assembly is likely required for BRCA2-Rad51 recruitment to damaged sites, allowing execution of homologous recombination repair. Recent studies suggest that the BRCA1-BARD1 heterodimer could also catalyze substrate monoubiquitination with substrate-specific E2s, such as UbcH6, Ube2e2, UbcM2, and Ube2w, as well as additional Lys63-linked polyubiquitin chains with Ubc13-Mms2. The substrate(s) and the timing of this action remain to be determined.