RRC ID 45368
Author Yasuhara T, Suzuki T, Katsura M, Miyagawa K.
Title Rad54B serves as a scaffold in the DNA damage response that limits checkpoint strength.
Journal Nat Commun
Abstract 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.
Volume 5
Pages 5426
Published 2014-11-11
DOI 10.1038/ncomms6426
PII ncomms6426
PMID 25384516
MeSH Cell Cycle Checkpoints / genetics Cell Cycle Checkpoints / physiology* Cell Line, Tumor DNA Damage / genetics DNA Damage / physiology* DNA Helicases / physiology* G1 Phase Cell Cycle Checkpoints / physiology G2 Phase Cell Cycle Checkpoints / physiology Humans M Phase Cell Cycle Checkpoints / physiology Nuclear Matrix / physiology* Nuclear Proteins / physiology* Proto-Oncogene Proteins c-mdm2 / physiology S Phase Cell Cycle Checkpoints / physiology Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / physiology*
IF 11.878
Times Cited 11
Human and Animal Cells