An association between the radiation-induced arrest of G2-phase cells and low-dose hyper-radiosensitivity:: A plausible underlying mechanism?

The survival of asynchronous and highly enriched G(1)-, Sand G(2)-phase populations of Chinese hamster V79 cells was measured after irradiation with Co-60 gamma rays (0.1-10 Gy) using a precise flow cytometry-based clonogenic survival assay. The high-dose survival responses demonstrated a conventional relationship, with G(2)-phase cells being the most radiosensitive and S-phase cells the most radioresistant. Below I Gy, distinct low-dose hyper-radiosensitivity (HRS) responses were observed for the asynchronous and G(2)-phase enriched cell populations, with no evidence of HRS in the G(1)- and S-phase populations. Modeling supports the conclusion that HRS in asynchronous V79 populations is explained entirely by the HRS response of G(2)-phase cells. An association was discovered between the occurrence of HRS and the induction of a novel G(2)-phase arrest checkpoint that is specific for cells that are in the G, phase of the cell cycle at the time of irradiation. Human T98G cells and hamster V79 cells, which both exhibit HRS in asynchronous cultures, failed to arrest the entry into mitosis of damaged G(2)-phase cells at doses less than 30 cGy, as determined by the flow cytometric assessment of the phosphorylation of histone 113, an established indicator of mitosis. In contrast, human U373 cells that do not show HRS induced this G(2)-phase checkpoint in a dose-independent manner. These data suggest that HRS may be a consequence of radiation-damaged G(2)-phase cells prematurely entering mitosis. (C) 2003 by Radiation Research Society.