Abstract
The evaluation of radiation-induced (RI) risks is of medical, scientific, and societal interest. However, despite considerable efforts, there is neither consensual mechanistic models nor predictive assays for describing the three major RI effects, namely radiosensitivity, radiosusceptibility, and radiodegeneration. Interestingly, the ataxia telangiectasia mutated (ATM) protein is a major stress response factor involved in the DNA repair and signaling that appears upstream most of pathways involved in the three precited RI effects. The rate of the RI ATM nucleoshuttling (RIANS) was shown to be a good predictor of radiosensitivity. In the frame of the RIANS model, irradiation triggers the monomerization of cytoplasmic ATM dimers, which allows ATM monomers to diffuse in nucleus. The nuclear ATM monomers phosphorylate the H2AX histones, which triggers the recognition of DNA double-strand breaks and their repair. The RIANS model has made it possible to define three subgroups of radiosensitivity and provided a relevant explanation for the radiosensitivity observed in syndromes caused by mutated cytoplasmic proteins. Interestingly, hyper-radiosensitivity to a low dose and adaptive response phenomena may be also explained by the RIANS model. In this review, the relevance of the RIANS model to describe several features of the individual response to radiation was discussed.
Highlights
To date, the evaluation of the risks linked to an exposure to radiation, whether clinical, occupational, or environmental, has become a societal, medical, and scientific issue
Normosensitivity: SF2 ranging from 50–70%, even up to 80% for some tumors, corresponds to individuals considered “radioresistant”, who do not suffer from cancer and who do not show any secondary effects after radiotherapy (CTCAE/Radiation Therapy Oncology Group (RTOG) grade 0) [2]
In 2016, from a collection of more than 100 human primary fibroblasts cell lines, it was hypothesized that ionizing radiation induces the monomerization of cytoplasmic ataxia telangiectasia mutated (ATM) dimers and triggers their diffusion in the nucleus to recognize double-strand breaks (DSB) and repair them via non-homologous end-joining pathway (NHEJ) [35,71]
Summary
The evaluation of the risks linked to an exposure to radiation, whether clinical, occupational, or environmental, has become a societal, medical, and scientific issue. The three major RI effects differ by their clinical features and their molecular origins, they share common points They obey specific dose-, time-, and dose-rate effect functions that are not necessarily linear and can present some thresholds [2,31]. Such dependence on both dose and time suggests that functional assays (i.e., those involving non-irradiated and irradiated cells) should be more suited to predicting the three major RI effects than the approaches derived from spontaneous data only (like DNA sequence, genomics, proteomics on non-irradiated cells). Threshold doses were reviewed in [2]
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