Influence of Linear Energy Transfer on the Nucleo-shuttling of the ATM Protein: A Novel Biological Interpretation Relevant for Particles and Radiation

Published on Mar 1, 2019in International Journal of Radiation Oncology Biology Physics5.859
· DOI :10.1016/J.IJROBP.2018.10.011
Mira Maalouf3
Estimated H-index: 3
(French Institute of Health and Medical Research),
Mira Maalouf1
Estimated H-index: 1
(French Institute of Health and Medical Research)
+ 10 AuthorsNicolas Foray30
Estimated H-index: 30
(French Institute of Health and Medical Research)
Sources
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.
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