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Influence of linear energy transfer on the nucleo-shuttling of the ATM protein: a novel biological interpretation relevant for particles and radiation.

PURPOSE: 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 breaks (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.

METHODS AND MATERIALS: 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.

RESULTS: 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, two fibroblast cell lines exposed to high-LET particles were shown to be protected by an accelerated ATM nucleo-shuttling.

CONCLUSIONS: Our findings are in agreement with the conclusion that LET and the radiation/particule 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. Altogether, 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.

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