How Ionizing Radiation Stops S Phase

Abstract

Falck et al. have made progress in defining the molecular mechanism underlying the S-phase checkpoint activated by ionizing radiation (IR). IR caused rapid, transient degradation of the phosphatase Cdc25A (which dephosphorylates and activates cyclin-dependent kinase 2) in mammalian cells by a mechanism dependent on the catalytic activity and the ability of the kinase Chk2 to interact with and phosphorylate Cdc25A. Furthermore, the degradation of Cdc25A in response to IR occurred in cells with normal and mutated versions of the tumor suppressor p53, confirming the independence of this S-phase checkpoint on the p53 pathway. However, in cells from patients with ataxia telangiectasia with mutations in the ATM gene, Cdc25A persisted after IR, and the cells exhibited radioresistant DNA synthesis. Thus, IR appears to activate a pathway from ATM to Chk2, which then phosphorylates Cdc25A leading to its destruction and a transient block in the progress of the S phase of the cell cycle. J. Falck, N. Mailand, R. G. Syljuåsen, J. Bartek, J. Lukas, The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410 , 842-847 (2001). [Online Journal]