The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
Research output: Contribution to journal › Journal article › Research › peer-review
When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. 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 gene. The Cdc25A phosphatase activates the cyclin-dependent kinase 2 (Cdk2) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Here we report a functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2) 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 alleles 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.
|Number of pages
|Published - 12 Apr 2001
- Alleles, Animals, Ataxia Telangiectasia Mutated Proteins, Cell Cycle, Cell Cycle Proteins, Cell Line, Checkpoint Kinase 2, DNA Replication, DNA-Binding Proteins, Humans, Mice, Phosphorylation, Protein Kinases, Protein-Serine-Threonine Kinases, Radiation Tolerance, Radiation, Ionizing, S Phase, Serine, Signal Transduction, Transfection, Tumor Suppressor Proteins, cdc25 Phosphatases