Cdc25-dependent activation of cyclin A/cdk2 is blocked in G2 phase arrested cells independently of ATM/ATR.
Cyclin A/cdk2 is active during S and G2 phases of the cell cycle, but its regulation and function during G2 phase is poorly understood. In this study we have examined the regulation of cyclin A/cdk2 activity during normal G2 phase progression and in genotoxin-induced G2 arrest. We show that cyclin A/cdk2 is activated in early G2 phase by a cdc25 activity. In the G2 phase checkpoint arrest initiated in response to various forms of DNA damage, the cdc25-dependent activation of both cyclin A/cdk2 and cyclin B1/cdc2 is blocked. Ectopic expression of cdc25B, but not cdc25C, in G2 phase arrested cells efficiently activated both cyclin A/cdk2 and cyclin B1/cdc2. Finally, we demonstrate that the block in cyclin A/cdk2 activation in the G2 checkpoint arrest is independent of ATM/ATR. We speculate that the ATM/ATR-independent block in G2 phase cyclin A/cdk2 activation may act as a further layer of checkpoint control, and that blocking G2 phase cyclin A/cdk2 activation contributes to the G2 phase checkpoint arrest.
Goldstone
S
S
Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, and Joint Experimental Oncology Program, Department of Pathology, University of Queensland, Brisbane, QLD, Australia.
Pavey
S
S
Forrest
A
A
Sinnamon
J
J
Gabrielli
B
B
D064007:Ataxia Telangiectasia Mutated Proteins; D042846:CDC2-CDC28 Kinases; D002110:Caffeine / Q000494:pharmacology; D018797:Cell Cycle Proteins; D019925:Cyclin A / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D016195:G2 Phase / Q000502:physiology*; D006801:Humans; D009153:Mutagens / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D020687:cdc25 Phosphatases / Q000378:metabolism*
D018797:Cell Cycle Proteins; D019925:Cyclin A; D004268:DNA-Binding Proteins; D009153:Mutagens; D025521:Tumor Suppressor Proteins; D002110:Caffeine; D005047:Etoposide; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D020687:cdc25 Phosphatases