Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736350/ https://www.ncbi.nlm.nih.gov/pubmed/29254517 http://dx.doi.org/10.7554/eLife.29953 |
_version_ | 1783287357781311488 |
---|---|
author | Wakida, Takeshi Ikura, Masae Kuriya, Kenji Ito, Shinji Shiroiwa, Yoshiharu Habu, Toshiyuki Kawamoto, Takuo Okumura, Katsuzumi Ikura, Tsuyoshi Furuya, Kanji |
author_facet | Wakida, Takeshi Ikura, Masae Kuriya, Kenji Ito, Shinji Shiroiwa, Yoshiharu Habu, Toshiyuki Kawamoto, Takuo Okumura, Katsuzumi Ikura, Tsuyoshi Furuya, Kanji |
author_sort | Wakida, Takeshi |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-5736350 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-57363502017-12-21 The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress Wakida, Takeshi Ikura, Masae Kuriya, Kenji Ito, Shinji Shiroiwa, Yoshiharu Habu, Toshiyuki Kawamoto, Takuo Okumura, Katsuzumi Ikura, Tsuyoshi Furuya, Kanji eLife Chromosomes and Gene Expression 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. eLife Sciences Publications, Ltd 2017-12-19 /pmc/articles/PMC5736350/ /pubmed/29254517 http://dx.doi.org/10.7554/eLife.29953 Text en © 2017, Wakida et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Chromosomes and Gene Expression Wakida, Takeshi Ikura, Masae Kuriya, Kenji Ito, Shinji Shiroiwa, Yoshiharu Habu, Toshiyuki Kawamoto, Takuo Okumura, Katsuzumi Ikura, Tsuyoshi Furuya, Kanji The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress |
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 | Chromosomes and Gene Expression |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736350/ https://www.ncbi.nlm.nih.gov/pubmed/29254517 http://dx.doi.org/10.7554/eLife.29953 |
work_keys_str_mv | AT wakidatakeshi thecdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT ikuramasae thecdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT kuriyakenji thecdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT itoshinji thecdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT shiroiwayoshiharu thecdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT habutoshiyuki thecdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT kawamototakuo thecdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT okumurakatsuzumi thecdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT ikuratsuyoshi thecdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT furuyakanji thecdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT wakidatakeshi cdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT ikuramasae cdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT kuriyakenji cdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT itoshinji cdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT shiroiwayoshiharu cdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT habutoshiyuki cdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT kawamototakuo cdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT okumurakatsuzumi cdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT ikuratsuyoshi cdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress AT furuyakanji cdkplk1axistargetsthednadamagecheckpointsensorproteinrad9topromotecellproliferationandtolerancetogenotoxicstress |