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

In cells exposed to low linear energy transfer (LET) ionizing-radiation (IR),double-strand-breaks (DSBs) form within clustered-damage-sites (CDSs) fromlesions disrupting the DNA sugar-phosphate backbone. It is commonly assumed thatall DSBs form promptly and are immediately detected by the cellularDNA-damage-response (DDR) apparatus. However, there is evidence that the pool ofDSBs detected by physical methods, such as pulsed-field gel electrophoresis(PFGE), comprises not only promptly forming DSBs (prDSBs) but also DSBsdeveloping during lysis at high temperatures from thermally-labile sugar-lesions(TLSLs). We recently demonstrated that conversion of TLSLs to DNA breaks andultimately to DSBs also occurs in cells during the first hour ofpost-irradiation incubation at physiological temperatures. Thus, TLSL-dependentDSBs (tlDSBs) are not an avoidable technique-related artifact, but a reality thecell always faces. The biological consequences of tlDSBs and the dependence oftheir formation on LET require in-depth investigation. Heavy-ions (HI) are apromising high-LET radiation modality used in cancer treatment. HI are alsoencountered in space and generate serious radiation protection problems toprolonged 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.