Function of BRCA1 in the DNA Damage Response Is Mediated by ADP-Ribosylation

• The BARD1 BRCT domain targets BRCA1 to DNA lesions during early DNA damage response
• The BARD1 BRCT domain is a PAR-binding domain
• PARP inhibitors suppress the fast recruitment of BRCA1 to DNA lesions
• PARP inhibition sensitizes the cells bearing mutations in the BRCA1 BRCT domain to IR

SummaryCarriers of BRCA1 germline mutations are predisposed to breast and ovarian cancers. Accumulated evidence shows that BRCA1 is quickly recruited to DNA lesions and plays an important role in the DNA damage response. However, the mechanism by which BRCA1 is recruited to DNA damage sites remains elusive. BRCA1 forms a Ring-domain heterodimer with BARD1, a major partner of BRCA1 that contains tandem BRCA1 C-terminus (BRCT) motifs. Here, we identify the BRCTs of BARD1 as a poly(ADP-ribose) (PAR)-binding module. The binding of the BARD1 BRCTs to PAR targets the BRCA1/BARD1 heterodimer to DNA damage sites. Thus, our study uncovers a PAR-dependent mechanism of rapid recruitment of BRCA1/BARD1 to DNA damage sites.

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