S6K1 phosphorylates components of the DNA repair machinery to orchestrate the DNA damage response.

The mTORC1 substrate, S6 Kinase 1 (S6K1), is known to be involved in the regulation of cell growth, ribosome biogenesis, glucose homeostasis and adipogenesis. Because the mTORC1 pathway promotes growth, survival and transformation, S6K1 has been considered a pro-oncogenic kinase. However, we showed previously, that under certain circumstances, S6K1 can act as a tumor suppressor and inhibit Ras-induced transformation. The molecular explanation for this activity has not been characterized. Here, we show that upon DNA damage, S6K1 shuttles into the nucleus, binds DNA repair proteins, regulating both mismatch DNA repair and homologous recombination. S6K1 orchestrates DNA repair by phosphorylation of Cdk1 (CDC2) at Ser39, causing G2/M cell cycle arrest, and MSH6, a mismatch repair (MMR) component, at the serine cluster S252,S254,S256. These phosphorylations correlate with reduced phosphorylation of γH2AX and increased MMR activity and Homologous Recombination Repair (HRR). Moreover, S6K1 increases the cell`s resistance to several DNA damaging agents and its expression is associated with poor survival of breast cancer patients treated with chemotherapy, but not patients that were not treated. Thus, S6K1 interaction with and phosphorylation of components of the DNA repair machinery may serve as a tumorigenic barrier, revealing S6K1 as an integrator between metabolic signals and the DNA damage response, safeguarding genomic stability.