S6K1 and S6K2 regulate homologous recombination DNA repair through control of BRCA1 protein stability

Recent studies have suggested that S6 kinase 1 (S6K1) contributes to DNA repair (DR). However, the specific pathways and mechanisms involved in this regulation remain unclear. Moreover, it has not been investigated whether S6K2, a functional homologue of S6K1, also contributes to DR. In this study, we investigated the function of both S6K1 and S6K2 (S6K1/2) proteins in DR and demonstrate that both are important for efficient Homologous Recombination-mediated repair (HR). Double knockout of S6K1/2 prevented the formation of BRCA1 and RAD51 foci and increases sensitivity to DNA-damaging agents such as PARP1 inhibitors, cisplatin, and X-ray irradiation. In addition, double knockout of S6K1/2 increased markers of genomic instability, while single knockout had little effect on HR markers and genome stability, which suggests that one kinase can compensate for the loss of the other. Mechanistically, we show that S6K1/2 regulate BRCA1 protein stability, limiting its degradation by the proteasome. Finally, pharmacological inhibition of S6K1/2 sensitised HR-proficient breast cancer cells to Olaparib. Our findings clarify the role of S6K1/2 proteins in HR and suggest that targeting these kinases may be a therapeutic strategy to enhance PARP inhibitor efficacy in HR-proficient tumours.