The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress
Takeshi Wakida,
Masae Ikura,
Kenji Kuriya,
Shinji Ito,
Yoshiharu Shiroiwa,
Toshiyuki Habu,
Takuo Kawamoto,
Katsuzumi Okumura,
Tsuyoshi Ikura,
Kanji Furuya
Affiliations
Takeshi Wakida
Department of Radiation Systems, Radiation Biology Center, Kyoto University, Kyoto, Japan; Laboratory of Chromatin Regulatory Network, Department of Mutagenesis, Radiation Biology Center, Kyoto University, Kyoto, Japan
Masae Ikura
Laboratory of Chromatin Regulatory Network, Department of Mutagenesis, Radiation Biology Center, Kyoto University, Kyoto, Japan
Kenji Kuriya
Laboratory of Nutritional Chemistry, Department of Life Sciences, Graduate School of Bioresources, Mie University, Tsu, Japan
Shinji Ito
Medical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Japan
Yoshiharu Shiroiwa
Department of Radiation Systems, Radiation Biology Center, Kyoto University, Kyoto, Japan
Toshiyuki Habu
Department of Radiation Systems, Radiation Biology Center, Kyoto University, Kyoto, Japan; Department of Food Science and Nutrition, Mukogawa Women’s University, Nishinomiya, Japan
Takuo Kawamoto
Radioisotope Research Center, Kyoto University, Kyoto, Japan
Katsuzumi Okumura
Laboratory of Molecular and Cellular Biology, Department of Life Sciences, Mie University, Tsu, Japan
Tsuyoshi Ikura
Laboratory 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, Japan
Department of Radiation Systems, Radiation Biology Center, Kyoto University, Kyoto, Japan; Laboratory of Genome Maintenance, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
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.
