Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Hufelandstr 55, Essen, 45122, Germany.
Radiat Oncol. 2013 Apr 2;8:77. doi: 10.1186/1748-717X-8-77.
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 the yields of tlDSBs and prDSBs. We report a reduction in the yield of tlDBSs stronger than that earlier reported for neutrons, and with pronounced cell line dependence. We conclude that with increasing LET the complexity of CDSs increases resulting in a commensurate increase in the yield prDSBs and a decrease in tlDSBs. The consequences of these effects to the relative biological effectiveness are discussed.
在暴露于低线性能量转移（LET）电离辐射（IR）的细胞中，双链断裂（DSBs）会在破坏 DNA 糖磷酸骨架的损伤部位（lesions）内形成簇状损伤部位（CDSs）。通常假设所有 DSBs 都会迅速形成，并立即被细胞 DNA 损伤反应（DDR）装置检测到。然而，有证据表明，物理方法（如脉冲场凝胶电泳（PFGE））检测到的 DSB 池不仅包括迅速形成的 DSBs（prDSBs），还包括在高温下从热不稳定糖损伤（TLSLs）中裂解时形成的 DSBs。我们最近证明，TLSLs 向 DNA 断裂并最终向 DSBs 的转化也会在生理温度下辐照后孵育的第一个小时内在细胞中发生。因此，TLSL 依赖性 DSBs（tlDSBs）不是不可避免的技术相关伪影，而是细胞始终面临的现实。tlDSBs 的生物学后果及其形成对 LET 的依赖性需要深入研究。重离子（HI）是一种有前途的高 LET 辐射方式，用于癌症治疗。HI 也在太空环境中遇到，并对长时间的太空任务产生严重的辐射防护问题。在这里，我们因此研究了 HI 对 tlDSBs 和 prDSBs 的产量的影响。我们报告了 tlDBSs 的产量减少，比以前报道的中子更强，并且具有明显的细胞系依赖性。我们得出结论，随着 LET 的增加，CDSs 的复杂性增加，导致 prDSBs 的产量增加，tlDSBs 的产量减少。讨论了这些效应对相对生物学效应的影响。
