The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
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- 12 April 2001
- journal article
- research article
- Published by Springer Nature in Nature
- Vol. 410 (6830), 842-847
- https://doi.org/10.1038/35071124
Abstract
When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle1,2,3. Defects in the IR-induced S-phase checkpoint cause ‘radioresistant DNA synthesis’, a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia, a disease caused by mutations in the ATM gene4,5,6. The Cdc25A phosphatase7 activates the cyclin-dependent kinase 2 (Cdk2) needed for DNA synthesis8,9, but becomes degraded in response to DNA damage10 or stalled replication11. Here we report a functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2)12 and Cdc25A, and implicate this mechanism in controlling the S-phase checkpoint. We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. An IR-induced loss of Cdc25A protein prevents dephosphorylation of Cdk2 and leads to a transient blockade of DNA replication. We also show that tumour-associated Chk2 alleles13 cannot bind or phosphorylate Cdc25A, and that cells expressing these Chk2 alleles, elevated Cdc25A or a Cdk2 mutant unable to undergo inhibitory phosphorylation (Cdk2AF) fail to inhibit DNA synthesis when irradiated. These results support Chk2 as a candidate tumour suppressor, and identify the ATM–Chk2–Cdc25A–Cdk2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.Keywords
This publication has 32 references indexed in Scilit:
- Rapid Destruction of Human Cdc25A in Response to DNA DamageScience, 2000
- DNA Damage-Induced Activation of p53 by the Checkpoint Kinase Chk2Science, 2000
- ATM: A mediator of multiple responses to genotoxic stressOncogene, 1999
- DNA Damage and Checkpoint Pathways: Molecular Anatomy and Interactions with RepairCell, 1998
- Requirements for p53 and the ATM gene product in the regulation of G1/S and S phase checkpointsOncogene, 1998
- Cdc25 Mitotic Inducer Targeted by Chk1 DNA Damage Checkpoint KinaseScience, 1997
- Cell Cycle Checkpoints: Preventing an Identity CrisisScience, 1996
- CDC25 Phosphatases as Potential Human OncogenesScience, 1995
- Cell Cycle Control and CancerScience, 1994
- Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: Evidence for multiple roles of mitotic cyclinsCell, 1991