INSERM, UMR 1052, Radiobiology Group, Cancer Research Centre of Lyon, Lyon, France; Lebanese University, Faculty of Sciences, Department of Chemistry and Biochemistry, Fanar, Beirut, Lebanon.
INSERM, UMR 1052, Radiobiology Group, Cancer Research Centre of Lyon, Lyon, France.
Int J Radiat Oncol Biol Phys. 2019 Mar 1;103(3):709-718. doi: 10.1016/j.ijrobp.2018.10.011. Epub 2018 Oct 19.
Linear energy transfer (LET) plays an important role in radiation response. Recently, the radiation-induced nucleo-shuttling of ATM from cytoplasm to the nucleus was shown to be a major event of the radiation response that permits a normal DNA double-strand break (DSB) recognition and repair. Here, we aimed to verify the relevance of the ATM nucleo-shuttling model for high-LET particles and various radiation types.
ATM- and H2AX-immunofluorescence was used to assess the number of recognized and unrepaired DSB in quiescent fibroblast cell lines exposed to x-rays, γ-rays, 9- and 12-MeV electrons, 3- and 65-MeV protons and 75-MeV/u carbon ions.
The rate of radiation-induced ATM nucleo-shuttling was found to be specific to each radiation type tested. By increasing the permeability of the nuclear membrane with statin and bisphosphonates, 2 fibroblast cell lines exposed to high-LET particles were shown to be protected by an accelerated ATM nucleo-shuttling.
Our findings are in agreement with the conclusion that LET and the radiation/particle type influence the formation of ATM monomers in cytoplasm that are required for DSB recognition. A striking analogy was established between the DSB repair kinetics of radioresistant cells exposed to high-LET particles and that of several radiosensitive cells exposed to low-LET radiation. Our data show that the nucleo-shuttling of ATM provides crucial elements to predict radiation response in human quiescent cells, whatever the LET value and their radiosensitivity.
线性能量转移（LET）在辐射反应中起着重要作用。最近，辐射诱导的 ATM 从细胞质到细胞核的核穿梭被证明是辐射反应的一个主要事件，它允许正常的 DNA 双链断裂（DSB）识别和修复。在这里，我们旨在验证 ATM 核穿梭模型对于高 LET 粒子和各种辐射类型的相关性。
使用 ATM 和 H2AX 免疫荧光来评估静息成纤维细胞系暴露于 X 射线、γ射线、9-MeV 和 12-MeV 电子、3-MeV 和 65-MeV 质子和 75-MeV/u 碳离子后识别和未修复的 DSB 数量。
发现辐射诱导的 ATM 核穿梭的速度取决于每种测试的辐射类型。通过用他汀类药物和双膦酸盐增加核膜的通透性，我们发现 2 种暴露于高 LET 粒子的成纤维细胞系通过加速的 ATM 核穿梭得到保护。
我们的发现与以下结论一致，即 LET 和辐射/粒子类型影响细胞质中 ATM 单体的形成，这些单体是 DSB 识别所必需的。在暴露于高 LET 粒子的耐辐射细胞和暴露于低 LET 辐射的几种 radiosensitive 细胞的 DSB 修复动力学之间建立了惊人的类比。我们的数据表明，ATM 的核穿梭为预测人类静息细胞的辐射反应提供了关键要素，无论 LET 值和它们的辐射敏感性如何。
