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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/79128 |
| _version_ | 1811230177465729024 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Adi Amar-Schwartz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T10:25:54Z |
| format | Article |
| id | doaj.art-415f0119bfe2430898b264371e2f1a67 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T10:25:54Z |
| publishDate | 2022-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-415f0119bfe2430898b264371e2f1a672022-12-22T03:36:58ZengeLife Sciences Publications LtdeLife2050-084X2022-10-011110.7554/eLife.79128S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repairAdi Amar-Schwartz0Vered Ben Hur1Amina Jbara2Yuval Cohen3Georgina D Barnabas4Eliran Arbib5Zahava Siegfried6https://orcid.org/0000-0001-9649-7434Bayan Mashahreh7https://orcid.org/0000-0002-1667-1322Fouad Hassouna8Asaf Shilo9Mohammad Abu-Odeh10Michael Berger11https://orcid.org/0000-0002-3469-0076Reuven Wiener12Rami Aqeilan13https://orcid.org/0000-0002-6034-023XTamar Geiger14https://orcid.org/0000-0002-9526-197XRotem Karni15https://orcid.org/0000-0002-7552-9617Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelDepartment of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelLautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelLautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelLautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelLautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelDepartment of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, IsraelThe 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.https://elifesciences.org/articles/79128S6K1MSH6DNA repairMSH2mTORC1CDK1 |
| spellingShingle | 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 S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair eLife S6K1 MSH6 DNA repair MSH2 mTORC1 CDK1 |
| title | S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair |
| title_full | S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair |
| title_fullStr | S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair |
| title_full_unstemmed | S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair |
| title_short | S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair |
| title_sort | s6k1 phosphorylates cdk1 and msh6 to regulate dna repair |
| topic | S6K1 MSH6 DNA repair MSH2 mTORC1 CDK1 |
| url | https://elifesciences.org/articles/79128 |
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