S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair

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 s...

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Published inbioRxiv
Main Authors Amar-Schwartz, Adi, Vered Ben Hur, Jbara, Amina, Cohen, Yuval, Barnabas, Georgina D, Zahava Siegfried, Mashahreh, Bayan, Hassouna, Fouad, Shilo, Asaf, Abu-Odeh, Mohammad, Berger, Michael, Wiener, Reuven, Aqeilan, Rami I, Geiger, Tamar, Karni, Rotem
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 27.03.2022
Subjects
Adipogenesis
Breast cancer
Cell cycle
Chemotherapy
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Gene amplification
Homeostasis
Homologous recombination
Homologous recombination repair
Kinases
MSH6 protein
Phosphorylation
Serine
Signal transduction
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Summary: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.
DOI:10.1101/2022.03.25.485744