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S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair
Adi Amar-Schwartz1, Vered Ben Hur1, Amina Jbara1
1Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Elife
|October 3, 2022
Summary
The study reveals that S6 Kinase 1 (S6K1) plays a crucial role in DNA repair by regulating cell cycle progression and enhancing homologous recombination and mismatch repair mechanisms. This discovery highlights S6K1
Area of Science:
- Molecular Biology
- Cellular Biology
- Cancer Research
Background:
- The mTORC1 signaling pathway is implicated in DNA damage response, but its direct role in DNA repair remains unclear.
- S6 Kinase 1 (S6K1), a key substrate of mTORC1, is known for regulating cell growth and metabolism.
Purpose of the Study:
- To investigate the direct role and mechanism of the mTORC1-S6K1 signaling pathway in DNA repair.
- To elucidate how S6K1 regulates homologous recombination (HR) and mismatch repair (MMR) pathways.
Main Methods:
- Investigated S6K1's role in DNA repair mechanisms.
- Analyzed the phosphorylation of Cdk1 and MSH6 by S6K1.
- Examined breast cancer cell lines with RPS6KB1 gene amplification.
- Correlated S6K1 expression with patient survival data.
Main Results:
- S6K1 orchestrates DNA repair by phosphorylating Cdk1 (at serine 39), inducing G2/M cell cycle arrest for homologous recombination.
- S6K1 enhances mismatch repair by phosphorylating MSH6 (at serine 309).
- Breast cancer cells with RPS6KB1 amplification exhibit resistance to DNA damaging agents, and high S6K1 expression correlates with poor chemotherapy outcomes.
Conclusions:
- S6K1 has a novel function in regulating DNA repair through cell cycle control, HRR, and MMR.
- S6K1 acts as a tumorigenic factor by maintaining genomic stability, potentially through DNA repair.
- Targeting S6K1 may offer therapeutic strategies for overcoming chemotherapy resistance in breast cancer.
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