The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis.

摘要: When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways delay the progression of cell cycle. Defects in IR-induced S-phase cause 'radioresistant DNA synthesis', a phenomenon that has been identified cancer-prone patients suffering from ataxia-telangiectasia, disease caused by mutations ATM gene. The Cdc25A phosphatase activates cyclin-dependent kinase 2 (Cdk2) needed for synthesis, but becomes degraded response damage or stalled replication. Here we report functional link between ATM, signalling Chk2/Cds1 (Chk2) and Cdc25A, implicate this mechanism controlling checkpoint. We show destruction requires both Chk2-mediated phosphorylation on serine 123. An loss protein prevents dephosphorylation Cdk2 leads transient blockade also tumour-associated Chk2 alleles cannot bind phosphorylate expressing these alleles, elevated mutant unable undergo inhibitory (Cdk2AF) fail inhibit synthesis when irradiated. These results support as candidate tumour suppressor, identify ATM-Chk2-Cdc25A-Cdk2 pathway genomic integrity radioresistant synthesis.