Regulation of the G2 cell-cycle checkpoints in response to low-dose ionizing radiation

In recent years, enhanced sensitivity in the radiation survival response of mammalian cells has been identified at doses below 0.5 Gray (Gy). Termed low-dose hyper-radiosensitivity (HRS), the response is typified by enhanced sensitivity of cells in the 0.1 and 0.2 Gy range, followed by increasing resistance to killing per unit dose up to 1.0 Gy where resistance becomes maximal per unit dose. This trend of an increase in radioresistance with dose is referred to as increased radioresistance (IRR) and the phenomenon of HRS/IRR has become well established and confirmed by several independent laboratories. However, the mechanism controlling the response of cells in the HRS/IRR dose region has yet to be identified. Current evidence has suggested that G2 phase cells and cell cycle checkpoints may be involved.;Improperly or un-repaired DNA double-strand breaks are the prime cause of cell death in response to ionizing radiation. To maintain genomic integrity, a number of cellular pathways have evolved which function to regulate and integrate responses to DNA damage through signal transduction cascades. Processes that govern cell cycle arrest, apoptosis and DNA repair all play roles in determining the particular sensitivity of a cell when exposed to radiation.;The discovery of a cell cycle arrest checkpoint regulated by DNA repair mediator ATM (Ataxia Telangtiectasia Mutated Protein) that is specific to G2 phase cells as well as the knowledge that DSBs may remain unrepaired after low-doses of radiation can all be linked to the concept of checkpoints and repair processes which are induced by doses in the HRS/IRR response region. Additionally, the use of protein specific inhibitors to modulate cell survival after low doses of ionizing radiation has helped elucidate which proteins are involved in these processes, and the establishment of a tie between p53-mediated cell apoptosis and low-dose hyper-radiosensitivity has provided an explanation for the fate of these sensitive cells. The work in our lab has indicated that understanding the mechanisms that control the detection, recognition and repair of radiation damage may lead to the determination of the radiobiological process that governs HRS/IRR, and profoundly impact treatment regimes in the future.