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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...

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Autores principales: Wakida, Takeshi, Ikura, Masae, Kuriya, Kenji, Ito, Shinji, Shiroiwa, Yoshiharu, Habu, Toshiyuki, Kawamoto, Takuo, Okumura, Katsuzumi, Ikura, Tsuyoshi, Furuya, Kanji
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
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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.
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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
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