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Cdc25-dependent activation of cyclin A/cdk2 is blocked in G2 phase arrested cells independently of ATM/ATR
S Goldstone1, S Pavey, A Forrest
1Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, and Joint Experimental Oncology Program, Department of Pathology, University of Queensland, Brisbane, QLD, Australia.
Abstract:
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.
Insights
Cyclin A/cdk2 activity during G2 phase is regulated by cdc25. DNA damage blocks this activation, suggesting a role in the G2 checkpoint control.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cyclin A/cdk2 plays a role in cell cycle regulation.
- Its function and regulation during the G2 phase remain unclear.
Purpose of the Study:
- To investigate the regulation of cyclin A/cdk2 activity during normal G2 phase progression.
- To understand its role in genotoxin-induced G2 arrest.
Main Methods:
- Examined cyclin A/cdk2 activity during G2 phase.
- Studied G2 arrest induced by DNA damage.
- Assessed the role of cdc25 isoforms (cdc25B, cdc25C) and ATM/ATR signaling.
Main Results:
- Cyclin A/cdk2 is activated in early G2 by cdc25.
- DNA damage-induced G2 arrest blocks cdc25-dependent activation of cyclin A/cdk2 and cyclin B1/cdc2.
- Ectopic expression of cdc25B, not cdc25C, reactivates both cyclin complexes.
- The block in activation is independent of ATM/ATR signaling.
Conclusions:
- The G2 checkpoint prevents cyclin A/cdk2 activation in a manner independent of ATM/ATR.
- This ATM/ATR-independent block may represent an additional layer of checkpoint control.
- Inhibition of G2 phase cyclin A/cdk2 activation contributes to the G2 checkpoint arrest.