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

Recent studies have suggested that the S6 kinase 1 (S6K1) contributes to DNA repair, specifically through the homologous recombination (HR) pathway. However, questions regarding the mechanism behind this regulation remain to be solved. Moreover, it has not yet been investigated whether S6K2, a protein homologous to S6K1 and with which it shares most of its functions, also contributes to the regulation of HR. Here, we investigated the relationship between S6K1 and S6K2 (S6K1/2) with DNA repair, and demonstrated that both are important for efficient HR. We showed that a single knockout of either S6K1 or S6K2 does not alter the HR function. However, double knockout of both S6K1/2 prevented the formation of BRCA1 and RAD51 foci, increased sensitivity to DNA damage, and increased markers of genomic instability. Our findings suggest that S6K1/2 present overlapping and compensatory functions regulating HR. Mechanistically, we demonstrated that S6K1/2 are important for maintaining BRCA1 protein stability, limiting its degradation by the proteasome. Finally, pharmacological inhibition of S6K1/2 sensitised HR-proficient breast cancer cells to olaparib, highlighting a potential therapeutic strategy to enhance PARP1 inhibitor efficacy in HR-proficient tumours.