S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair

Adi Amar-Schwartz, Vered Ben Hur, Amina Jbara, Yuval Cohen, Georgina D. Barnabas, Eliran Arbib, Zahava Siegfried, Bayan Mashahreh, Fouad Hassouna, Asaf Shilo, Mohammad Abu-Odeh, Michael Berger, Reuven Wiener, Rami Aqeilan, Tamar Geiger, Rotem Karni*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 orches-trates 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.

Original languageAmerican English
Article numbere79128
JournaleLife
Volume11
DOIs
StatePublished - 3 Oct 2022

Bibliographical note

Publisher Copyright:
© Amar-Schwartz, Ben Hur, Jbara et al.

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