TY - JOUR TI - S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair AU - Amar-Schwartz, Adi AU - Ben Hur, Vered AU - Jbara, Amina AU - Cohen, Yuval AU - Barnabas, Georgina D AU - Arbib, Eliran AU - Siegfried, Zahava AU - Mashahreh, Bayan AU - Hassouna, Fouad AU - Shilo, Asaf AU - Abu-Odeh, Mohammad AU - Berger, Michael AU - Wiener, Reuven AU - Aqeilan, Rami AU - Geiger, Tamar AU - Karni, Rotem A2 - Sonenberg, Nahum A2 - Tyler, Jessica K VL - 11 PY - 2022 DA - 2022/10/03 SP - e79128 C1 - eLife 2022;11:e79128 DO - 10.7554/eLife.79128 UR - https://doi.org/10.7554/eLife.79128 AB - The mTORC1 substrate, S6 Kinase 1 (S6K1), is involved in the regulation of cell growth, ribosome biogenesis, glucose homeostasis, and adipogenesis. Accumulating evidence has suggested a role for mTORC1 signaling in the DNA damage response. This is mostly based on the findings that mTORC1 inhibitors sensitized cells to DNA damage. However, a direct role of the mTORC1-S6K1 signaling pathway in DNA repair and the mechanism by which this signaling pathway regulates DNA repair is unknown. In this study, we discovered a novel role for S6K1 in regulating DNA repair through the coordinated regulation of the cell cycle, homologous recombination (HR) DNA repair (HRR) and mismatch DNA repair (MMR) mechanisms. Here, we show that S6K1 orchestrates DNA repair by phosphorylation of Cdk1 at serine 39, causing G2/M cell cycle arrest enabling homologous recombination and by phosphorylation of MSH6 at serine 309, enhancing MMR. Moreover, breast cancer cells harboring RPS6KB1 gene amplification show increased resistance to several DNA damaging agents and S6K1 expression is associated with poor survival of breast cancer patients treated with chemotherapy. Our findings reveal an unexpected function of S6K1 in the DNA repair pathway, serving as a tumorigenic barrier by safeguarding genomic stability. KW - S6K1 KW - MSH6 KW - DNA repair KW - MSH2 KW - mTORC1 KW - CDK1 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -