Abstract
“Dose-rate effect” was known as a result of sub-lethal damage repair during chronic irradiation. However, there has not yet been well described the molecular mechanism of DNA double-strand break (DSB) repair under low dose-rate irradiation. In higher vertebrate cells, there are at least two major DSB repair pathways, namely non-homologous end-joining (NHEJ) and homologous recombination (HR). To elucidate the role of DSB repair mechanism in cellular dose-rate effect, the cellular sensitivity to low dose-rate radiation is investigating using DSB repair-defective cell lines. In chicken DT40 cells irradiated with γ-rays at a low dose-rate, NHEJ-related KU70-defective cells showed higher sensitivity than HR-related RAD54-defective cells and RAD54-/-KU70-/- cells. Next, we analyzed the causative cellular process of our obtained results at the Radiation Biology Center, Kyoto University. At 0.1 Gy/h, KU70-/- cells showed significant G2 arrest in comparison with RAD54-/- and RAD54-/-KU70-/- cells, following the induction of apoptosis.
We also analyzed the surviving fraction of human glioblastoma DNA-PKcs-defective cells after low-dose rate irradiation. The surviving fraction decreased gradually and leveled off after 3 weeks irradiation, suggesting cell turnover is one of the important factors under low dose-rate irradiation condition.
When considering the effect of low dose-rate irradiation to the living tissue, the accumulation of DNA damage in tissue stem cells is one of the important issues. Nijnik et al. (Nature, 2007) reported that diminished DSB repair in the Lig4 mutated mouse strain causes a progressive loss of hematopoietic stem cells during ageing. The importance of DSB repair mechanisms in the tissues under low dose-rate irradiation condition will be discussed based on our obtained results.
