Mira Maalouf1, Adeline Granzotto2, Clément Devic2, Larry Bodgi3, Mélanie Ferlazzo2, Christophe Peaucelle4, Marcel Bajard4, Jean-Yves Giraud5, Jacques Balosso5, Joël Hérault6, Marie-Claude Biston7, Claude Malet7, Nicolas Foray8. 1. 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. 2. INSERM, UMR 1052, Radiobiology Group, Cancer Research Centre of Lyon, Lyon, France. 3. INSERM, UMR 1052, Radiobiology Group, Cancer Research Centre of Lyon, Lyon, France; American University of Beirut Medical Center, Department of Radiation Oncology, Riad El Solh, Ras Beirut, Beirut, Lebanon. 4. CNRS, Nuclear Physics Institute of Lyon, University Lyon 1, Villeurbanne, France. 5. University of Grenoble-Alpes, University Hospital of Grenoble, Radiation Oncology and Radiophysics Department, La Tronche, France. 6. Anti-cancer Center Antoine-Lacassagne, Nice, France. 7. Anti-cancer Center Léon-Bérard, Lyon, France. 8. INSERM, UMR 1052, Radiobiology Group, Cancer Research Centre of Lyon, Lyon, France. Electronic address: Nicolas.foray@inserm.fr.
Abstract
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 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. 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, 2 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/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.
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 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. 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, 2 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/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.