Defective homologous recombination repair (HRR) due to BRCA1 loss of function

The N-terminal region of BRCA1 contains the RING domain (residues 7-98), required for the heterodimerization of BRCA1 with BARD1. BRCA1:BARD1 heterodimer has E3 ubiquitin ligase activity which is important for DNA repair. Several missense mutations within the RING domain have been linked to increased risks of developing breast/ovarian cancers. BRCA1 mutant proteins impaired in BARD1 binding are annotated in the pathway "Defective DNA double strand break response due to BRCA1 loss of function".

The C-terminal region of BRCA1 which contains two coiled coil domains (residues 1397-1424) and two BRCT domains (residues 1642-1736 for BRCT 1; residues 1756-1855 for BRCT 2) is involved in PALB2 binding, with the second coiled coil domain being essential. Several cancer-associated BRCA1 missense mutants that affect the C-terminal region were shown to have reduced ability to bind PALB2. In addition, many nonsense and frameshift mutations in BRCA1 reported in cancer result in truncated proteins that lack the PALB2-binding domain.