Breast cancer type 1 susceptibility protein-BRCA1-associated RING domain protein 1 heterodimer interface (BRCA1-BARD1 interface)

The BRCA1-BARD1 heterodimer interface is a critical protein-protein interaction site between the Breast cancer type 1 susceptibility protein (BRCA1) and the BRCA1-associated RING domain protein 1 (BARD1). This interaction, mediated by their respective N-terminal RING domains, is essential for the structural stability of BRCA1 and its function as an E3 ubiquitin ligase (Brzovic et al., 2001, Nature Structural Biology). Biologically, the heterodimer is a central component of the DNA damage response, facilitating the repair of double-strand breaks through homologous recombination (HR) (Witus et al., 2021, Nature Communications). Loss of this interaction due to genetic mutations is a well-documented driver of hereditary breast, ovarian, and other cancers, leading to genomic instability (Starita et al., 2004, Journal of Biological Chemistry). In drug discovery, the interface is being explored as a therapeutic target for small-molecule inhibitors and peptide mimetics that aim to disrupt the complex. By inhibiting this interaction, researchers hope to induce a state of "BRCA-ness" in tumor cells, thereby sensitizing them to PARP inhibitors or conventional DNA-damaging agents through synthetic lethality (Caldwell et al., 2022, RSC Chemical Biology).

Other names

BRCA1/BARD1 complexBRCA1-BARD1 RING domain heterodimerBRCA1-BARD1 E3 ligase complexBRCA1-BARD1 RING-RING interface

Disruption of protein-protein interaction (PPI) to inhibit E3 ligase activity and destabilize BRCA1, leading to impaired homologous recombination and sensitization to DNA-damaging agents.