Induction of Cdc25B regulates cell cycle resumption after genotoxic stress.
Cdc25 phosphatases propel cell cycle progression by activating cyclin-dependent kinases (Cdk). DNA damage is generally thought to inhibit Cdc25 functionality by inducing proteasomal degradation of Cdc25A and phosphorylation-mediated sequestration of Cdc25B and Cdc25C to the cytoplasm. More recently, a critical role for Cdc25B in the resumption of cell cycle progression through mitosis after DNA damage has been identified. In this study, the fate of Cdc25B after mechanistically distinct DNA-damaging agents (etoposide, cisplatin, bleomycin, ionizing irradiation, or UV irradiation) was examined, and surprisingly a rapid increase in cellular Cdc25B levels was observed after DNA damage. Using UV irradiation as the prototypic damaging agent, we found that the increase in Cdc25B levels was checkpoint dependent and was controlled by a p53-independent mechanism. Cdc25B levels controlled the number of cells progressing into mitosis after UV, but they did not affect G(2)-M checkpoint engagement immediately after DNA damage. Increased Cdc25B reduced the time required for cell cycle resumption. These data support a model in which Cdc25B accumulation is an important anticipatory event for cell cycle resumption after DNA damage.
Bansal
Pallavi
P
Department of Pharmacology, University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Lazo
John S
JS
D001761:Bleomycin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology / Q000528:radiation effects; D014466:Ultraviolet Rays; D020687:cdc25 Phosphatases / Q000096:biosynthesis*
D018797:Cell Cycle Proteins; D001761:Bleomycin; D005047:Etoposide; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases; D002945:Cisplatin