BRC8 Overexpression Hyperstabilizes RAD51, Paradoxically Reducing Homologous Recombination and Increasing DNA Damage Sensitivity

Genomic stability is critically maintained by homologous recombination (HR), a DNA repair pathway where RAD51 plays an essential role. Aberrant RAD51 expression compromises genomic integrity and influences cellular responses to DNA-damaging agents, with increased RAD51 often linked to therapeutic resistance and poor prognosis in various cancers. BRCA2, a key tumor suppressor, promotes HR by interacting with RAD51 via eight BRC repeats (BRC1-8). While these repeats share low sequence similarity, previous work suggested individual BRC repeats distinctly affect RAD51 expression, highlighting a gap in understanding which specific repeats modulate RAD51 protein levels and function.

Researchers investigated the effects of BRC8 overexpression in cellular models to identify specific BRC repeat regions affecting RAD51 protein levels and DNA repair dynamics. They assessed RAD51 protein levels, foci formation (a marker of RAD51 recruitment to DNA damage sites), homologous recombination (HR) repair efficiency, and cellular sensitivity to DNA-damaging agents. The study aimed to elucidate how individual BRC repeats, particularly BRC8, modulate RAD51 expression and stability, and consequently, DNA repair outcomes.

Overexpression of BRC8 significantly elevated RAD51 protein levels and foci formation in cells. This stabilization was attributed to BRC8 inhibiting ubiquitin-mediated degradation of RAD51. > Paradoxically, despite the increased RAD51 foci, BRC8 expression significantly reduced HR repair efficiency and increased cellular sensitivity to DNA-damaging agents. These findings suggest that while BRC8 stabilizes RAD51, it impairs the timely removal of RAD51 from DNA damage sites, leading to dysfunctional HR. Additionally, altered cell cycle distribution was observed, which may contribute to reduced non-homologous end-joining (NHEJ) efficiency, further enhancing cellular vulnerability to DNA damage.