The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress
Genotoxic stress causes proliferating cells to activate the DNA damage checkpoint, to assist DNA damage recovery by slowing cell cycle progression. Thus, to drive proliferation, cells must tolerate DNA damage and suppress the checkpoint response. However, the mechanism underlying this negative regul...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/29953 |
| _version_ | 1811236862349541376 |
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| author | Takeshi Wakida Masae Ikura Kenji Kuriya Shinji Ito Yoshiharu Shiroiwa Toshiyuki Habu Takuo Kawamoto Katsuzumi Okumura Tsuyoshi Ikura Kanji Furuya |
| author_facet | Takeshi Wakida Masae Ikura Kenji Kuriya Shinji Ito Yoshiharu Shiroiwa Toshiyuki Habu Takuo Kawamoto Katsuzumi Okumura Tsuyoshi Ikura Kanji Furuya |
| author_sort | Takeshi Wakida |
| collection | DOAJ |
| description | Genotoxic stress causes proliferating cells to activate the DNA damage checkpoint, to assist DNA damage recovery by slowing cell cycle progression. Thus, to drive proliferation, cells must tolerate DNA damage and suppress the checkpoint response. However, the mechanism underlying this negative regulation of checkpoint activation is still elusive. We show that human Cyclin-Dependent-Kinases (CDKs) target the RAD9 subunit of the 9-1-1 checkpoint clamp on Thr292, to modulate DNA damage checkpoint activation. Thr292 phosphorylation on RAD9 creates a binding site for Polo-Like-Kinase1 (PLK1), which phosphorylates RAD9 on Thr313. These CDK-PLK1-dependent phosphorylations of RAD9 suppress checkpoint activation, therefore maintaining high DNA synthesis rates during DNA replication stress. Our results suggest that CDK locally initiates a PLK1-dependent signaling response that antagonizes the ability of the DNA damage checkpoint to detect DNA damage. These findings provide a mechanism for the suppression of DNA damage checkpoint signaling, to promote cell proliferation under genotoxic stress conditions. |
| first_indexed | 2024-04-12T12:15:21Z |
| format | Article |
| id | doaj.art-24020094897e44068e56559515ee3845 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:15:21Z |
| publishDate | 2017-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-24020094897e44068e56559515ee38452022-12-22T03:33:26ZengeLife Sciences Publications LtdeLife2050-084X2017-12-01610.7554/eLife.29953The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stressTakeshi Wakida0Masae Ikura1Kenji Kuriya2Shinji Ito3Yoshiharu Shiroiwa4Toshiyuki Habu5Takuo Kawamoto6Katsuzumi Okumura7Tsuyoshi Ikura8Kanji Furuya9https://orcid.org/0000-0002-5099-8302Department of Radiation Systems, Radiation Biology Center, Kyoto University, Kyoto, Japan; Laboratory of Chromatin Regulatory Network, Department of Mutagenesis, Radiation Biology Center, Kyoto University, Kyoto, JapanLaboratory of Chromatin Regulatory Network, Department of Mutagenesis, Radiation Biology Center, Kyoto University, Kyoto, JapanLaboratory of Nutritional Chemistry, Department of Life Sciences, Graduate School of Bioresources, Mie University, Tsu, JapanMedical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, JapanDepartment of Radiation Systems, Radiation Biology Center, Kyoto University, Kyoto, JapanDepartment of Radiation Systems, Radiation Biology Center, Kyoto University, Kyoto, Japan; Department of Food Science and Nutrition, Mukogawa Women’s University, Nishinomiya, JapanRadioisotope Research Center, Kyoto University, Kyoto, JapanLaboratory of Molecular and Cellular Biology, Department of Life Sciences, Mie University, Tsu, JapanLaboratory of Chromatin Regulatory Network, Department of Mutagenesis, Radiation Biology Center, Kyoto University, Kyoto, Japan; Laboratory of Chromatin Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto, JapanDepartment of Radiation Systems, Radiation Biology Center, Kyoto University, Kyoto, Japan; Laboratory of Genome Maintenance, Graduate School of Biostudies, Kyoto University, Kyoto, JapanGenotoxic stress causes proliferating cells to activate the DNA damage checkpoint, to assist DNA damage recovery by slowing cell cycle progression. Thus, to drive proliferation, cells must tolerate DNA damage and suppress the checkpoint response. However, the mechanism underlying this negative regulation of checkpoint activation is still elusive. We show that human Cyclin-Dependent-Kinases (CDKs) target the RAD9 subunit of the 9-1-1 checkpoint clamp on Thr292, to modulate DNA damage checkpoint activation. Thr292 phosphorylation on RAD9 creates a binding site for Polo-Like-Kinase1 (PLK1), which phosphorylates RAD9 on Thr313. These CDK-PLK1-dependent phosphorylations of RAD9 suppress checkpoint activation, therefore maintaining high DNA synthesis rates during DNA replication stress. Our results suggest that CDK locally initiates a PLK1-dependent signaling response that antagonizes the ability of the DNA damage checkpoint to detect DNA damage. These findings provide a mechanism for the suppression of DNA damage checkpoint signaling, to promote cell proliferation under genotoxic stress conditions.https://elifesciences.org/articles/29953U2OSHEK293culture cell |
| spellingShingle | Takeshi Wakida Masae Ikura Kenji Kuriya Shinji Ito Yoshiharu Shiroiwa Toshiyuki Habu Takuo Kawamoto Katsuzumi Okumura Tsuyoshi Ikura Kanji Furuya The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress eLife U2OS HEK293 culture cell |
| title | The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress |
| title_full | The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress |
| title_fullStr | The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress |
| title_full_unstemmed | The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress |
| title_short | The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress |
| title_sort | cdk plk1 axis targets the dna damage checkpoint sensor protein rad9 to promote cell proliferation and tolerance to genotoxic stress |
| topic | U2OS HEK293 culture cell |
| url | https://elifesciences.org/articles/29953 |
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