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

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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Carbon / chemistry
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Survival
  • DNA Breaks, Double-Stranded*
  • DNA Damage
  • DNA Repair*
  • Fibroblasts / radiation effects
  • Gamma Rays
  • Histones / metabolism
  • Humans
  • Ions
  • Kinetics
  • Linear Energy Transfer*
  • Microscopy, Fluorescence
  • Permeability
  • Protons
  • Radiation Tolerance*
  • Radiometry


  • H2AX protein, human
  • Histones
  • Ions
  • Protons
  • Carbon
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins