Reduced contribution of thermally labile sugar lesions to DNA double strand breakformation after exposure to heavy ions

摘要

In cells exposed to low linear energy transfer (LET) ionizing-radiation (IR), double-strand-breaks (DSBs) form within clustered-damage-sites (CDSs) from lesions disrupting the DNA sugar-phosphate backbone. It is commonly assumed that all DSBs form promptly and are immediately detected by the cellular DNA-damage-response (DDR) apparatus. However, there is evidence that the pool of DSBs detected by physical methods, such as pulsed-field gel electrophoresis (PFGE), comprises not only promptly forming DSBs (prDSBs) but also DSBs developing during lysis at high temperatures from thermally-labile sugar-lesions (TLSLs). We recently demonstrated that conversion of TLSLs to DNA breaks and ultimately to DSBs also occurs in cells during the first hour of post-irradiation incubation at physiological temperatures. Thus, TLSL-dependent DSBs (tlDSBs) are not an avoidable technique-related artifact, but a reality the cell always faces. The biological consequences of tlDSBs and the dependence of their formation on LET require in-depth investigation. Heavy-ions (HI) are a promising high-LET radiation modality used in cancer treatment. HI are also encountered in space and generate serious radiation protection problems to prolonged space missions. Here, we study, therefore, the effect of HI on theyields of tlDSBs and prDSBs. We report a reduction in the yield of tlDBSsstronger than that earlier reported for neutrons, and with pronounced cell linedependence. We conclude that with increasing LET the complexity of CDSsincreases resulting in a commensurate increase in the yield prDSBs and adecrease in tlDSBs. The consequences of these effects to the relative biologicaleffectiveness are discussed.