Rad54B serves as a scaffold in the DNA damage response that limits checkpoint strength.
The strength of the DNA damage checkpoint critically influences cell fate, yet the mechanisms behind the fine tuning of checkpoint strength during the DNA damage response (DDR) are poorly understood. Here we show that Rad54B--a SNF2 helicase-like DNA-repair protein--limits the strength of both the G1/S and G2/M checkpoints. We find that Rad54B functions as a scaffold for p53 degradation via its direct interaction with the MDM2-MDMX ubiquitin-ligase complex. During the early phases of the DDR, Rad54B is upregulated, thereby maintaining low checkpoint strength and facilitating cell cycle progression. Once the p53-mediated checkpoint is established, Rad54B is downregulated, and high checkpoint strength is maintained. Constitutive upregulation of Rad54B activity, which is frequently observed in tumours, promotes genomic instability because of checkpoint override. Thus, the scaffolding function of Rad54B dynamically regulates the maintenance of genome integrity by limiting checkpoint strength.
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Takaaki
T
Yasuhara
Department of Radiological Technology, Faculty of Medical Technology, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Takahiko
T
Suzuki
Isotope Science Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Mari
M
Katsura
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Kiyoshi
K
Miyagawa
D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D004265:DNA Helicases / Q000502:physiology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000502:physiology; D059565:G2 Phase Cell Cycle Checkpoints / Q000502:physiology; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology; D015530:Nuclear Matrix / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D059807:S Phase Cell Cycle Checkpoints / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D009687:Nuclear Proteins; C491221:RAD54B protein, human; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D004265:DNA Helicases