Abstract
Low-dose hyper-radiosensitivity (HRS) is the increased sensitivity of mammalian cells to acute radiation doses below ~40 cGy. As the dose increases above 40 cGy, increasing levels of DNA damage produce increased radioresistance (IRR). The transition from HRS to IRR is determined by cell-cycle related events involving the ATM-dependent G2-phase cell-cycle checkpoint (ATM-G2-check). Specifically, G2-phase cells that receive low-dose radiation exposure in the HRS region evade the ATM-G2-check, exhibit reduced fidelity of DNA repair and have an elevated risk of dying when they proceed unchecked into mitosis. HRS is associated with an increase in DNA double-strand breaks in G2/M phase cells and slower repair, and there is a correspondence between HRS and post-mitotic caspase-3 mediated apoptosis. At higher radiation doses, in the IRR region, the ATM-G2-check is activated in response to radiation-induced DNA double-strand breaks via ATM-mediated events, allowing cells irradiated in G2 to more effectively repair DNA damage before entering mitosis, which is reflected by an increase in net radioresistance per unit dose. HRS also manifests as a strong inverse dose rate effect in cycling cell populations exposed to continuous irradiation at less than ~60 cGy h-1. Also in this case, the lack of an ATM-G2-check can be demonstrated. These observations provide a compelling case for exploring radiotherapeutic strategies based on HRS, and for building low-dose hypersensitivity into the radiotherapy treatment planning process, and for re-evaluating low-dose radiation risk estimates.
