Marples, B., Wouters, B. G. and Joiner, M. C. An Association between the Radiation-Induced Arrest of G₂-Phase Cells and Low-Dose Hyper-Radiosensitivity: A Plausible Underlying Mechanism? Radiat. Res. 160, 38–45 (2003).

The survival of asynchronous and highly enriched G₁-, S- and G₂-phase populations of Chinese hamster V79 cells was measured after irradiation with ⁶⁰Co γ rays (0.1–10 Gy) using a precise flow cytometry-based clonogenic survival assay. The high-dose survival responses demonstrated a conventional relationship, with G₂-phase cells being the most radiosensitive and S-phase cells the most radioresistant. Below 1 Gy, distinct low-dose hyper-radiosensitivity (HRS) responses were observed for the asynchronous and G₂-phase enriched cell populations, with no evidence of HRS in the G₁- and S-phase populations. Modeling supports the conclusion that HRS in asynchronous V79 populations is explained entirely by the HRS response of G₂-phase cells. An association was discovered between the occurrence of HRS and the induction of a novel G₂-phase arrest checkpoint that is specific for cells that are in the G₂ 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 G₂-phase cells at doses less than 30 cGy, as determined by the flow cytometric assessment of the phosphorylation of histone H3, an established indicator of mitosis. In contrast, human U373 cells that do not show HRS induced this G₂-phase checkpoint in a dose-independent manner. These data suggest that HRS may be a consequence of radiation-damaged G₂-phase cells prematurely entering mitosis.