Proteolysis of Rad17 by Cdh1/APC regulates checkpoint termination and recovery from genotoxic stress.
Recent studies have shown a critical function for the ubiquitin-proteasome system (UPS) in regulating the signalling network for DNA damage responses and DNA repair. To search for new UPS targets in the DNA damage signalling pathway, we have carried out a non-biased assay to identify fast-turnover proteins induced by various types of genotoxic stress. This endeavour led to the identification of Rad17 as a protein exhibiting a distinctive pattern of upregulation followed by subsequent degradation after exposure to UV radiation in human primary cells. Our characterization showed that UV-induced Rad17 oscillation is mediated by Cdh1/APC, a ubiquitin-protein ligase. Studies using a degradation-resistant Rad17 mutant demonstrated that Rad17 stabilization prevents the termination of checkpoint signalling, which in turn attenuates the cellular re-entry into cell-cycle progression. The findings provide an insight into how the proteolysis of Rad17 by Cdh1/APC regulates the termination of checkpoint signalling and the recovery from genotoxic stress.
Zhang
Liyong
L
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Park
Chi-Hoon
CH
Wu
Jing
J
Kim
Hyun
H
Liu
Weijun
W
Fujita
Takeo
T
Balasubramani
Manimalha
M
Schreiber
Emanuel M
EM
Wang
Xiao-Fan
XF
Wan
Yong
Y
D015703:Antigens, CD; D064007:Ataxia Telangiectasia Mutated Proteins; D015820:Cadherins / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009991:Oscillometry / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D015703:Antigens, CD; D064007:Ataxia Telangiectasia Mutated Proteins; D015820:Cadherins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C513384:CDH1 protein, human; C113575:Rad17 protein, human; C576324:ATM protein, human; C576597:ATR protein, human