RAD51 recombinase-Breast cancer type 2 susceptibility protein interface (RAD51-BRCA2 PPI) (RAD51-BRCA2 PPI)

The RAD51-BRCA2 protein-protein interface is a vital regulatory site within the homologous recombination (HR) DNA repair pathway. BRCA2 acts as a scaffold, employing its eight conserved BRC repeats to bind RAD51 and direct its assembly into helical nucleoprotein filaments on single-stranded DNA (ssDNA) (Pellegrini et al., 2002, Nature; UniProt P38398). This filament formation is the rate-limiting step for strand invasion and subsequent error-free repair of double-strand breaks (DSBs) (Davies et al., 2001, Molecular Cell). Disruption of this interface prevents the localization of RAD51 to DNA damage sites, leading to genomic instability and cell death (UniProt Q06609). In clinical oncology, this interface is targeted to overcome resistance to PARP inhibitors or to sensitize tumors to conventional DNA-damaging agents like cisplatin and ionizing radiation. Small molecule inhibitors, such as CAM833, have been designed to competitively bind the RAD51 surface normally occupied by BRCA2 BRC repeats, thereby potently inhibiting HR (Scott et al., 2021, Nature Communications). This therapeutic approach exploits the dependency of cancer cells on HR, particularly in the context of synthetic lethality or combination therapy.

Other names

BRCA2-RAD51 interactionBRC repeat-RAD51 interfaceRAD51-BRCA2 complexBRCA2-RAD51 PPI

Inhibition of the interaction between BRCA2 BRC repeats and RAD51, preventing the assembly of RAD51 nucleoprotein filaments on single-stranded DNA.