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Review
. 2019 Jun 28;11(7):905.
doi: 10.3390/cancers11070905.

The Nucleoshuttling of the ATM Protein: A Unified Model to Describe the Individual Response to High- and Low-Dose of Radiation?

Elise Berthel  1 , Nicolas Foray  2 , Mélanie L Ferlazzo  1
Affiliations
Review

The Nucleoshuttling of the ATM Protein: A Unified Model to Describe the Individual Response to High- and Low-Dose of Radiation?

Elise Berthel et al. Cancers (Basel). .

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.

Keywords: ATM; DSB repair; radiosensitivity.

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Conflict of interest statement

N.F. is co-founder and the scientific advisers of the Neolys Diagnostics start-up company that developed predictive assays. A conventional agreement between the academic UA8 Inserm unit and Neolys Diagnostics has been validated by the Deontology Commission of INSERM. It is noteworthy that this company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results”.

Figures

Figure 1
Figure 1
The major radiation-induced (RI) effects and their specific features. This figure aims to summarize the current basic knowledge of radiosensitivity, radiosusceptibility, and radiodegeneration. The threshold doses were reviewed in [2].
Figure 2
Figure 2
Cellular radiosensitivity as a function of syndrome prevalence. Survival fraction at 2 Gy (SF2) was fixed at 1% for ataxia telangiectasia mutated (ATM)-mutated cells and 100% for normosensitive patients. Each syndrome is represented by confidence zones. Data were taken from the databank of our lab and from [39].
Figure 3
Figure 3
The radiation-induced ATM nucleoshuttling (RIANS) model and its applications. (A) Representative image of pATM immunofluorescence before or after irradiation (2 Gy) in human normosensitive control fibroblast cell lines. (B) Schematic illustration of the three groups of radiosensitivity defined from the RIANS model. (C) Schematic illustration of the hyperradiosensitivity to low doses (HRS) and the adaptive response (AR) phenomena and of the effect of the combination of statins and bisphosphonates (zoledronate+pravastatin, (ZOPRA)) on the RIANS. Since the link between radiosensitivity and the nuclear membrane permeability is still unknown, membranes are represented in the same manner.
See this image and copyright information in PMC

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