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Human Radiosensitivity, Radiosusceptibility and Radiodegeneration
The individual response to ionizing radiation may show several clinical features such as skin burns, cancers or cataracts, according the tissue type, the genetic status or the dose. To avoid any confusion with a non-univocal way of using the term “radiosensitivity”, we have proposed the following definitions :
- “Radiosensitivity is the proneness to the radiation-induced adverse tissue events generally attributable to cell death that is correlated with unrepaired DNA damage.
-“Radiosusceptibilty” is the proneness to the radiation-induced cancers generally attributable to cell transformation that is correlated with misrepaired DNA damage.
-"Radiodegeneration" is the proneness to radiation-induced non-cancer effects attributable to mechanisms related to accelerated aging that is correlated with the accumulation of tolerated unrepaired DNA damage.
The individual response to ionizing radiation (IR) raises a number of medical, scientific, and societal issues. While the term “radiosensitivity” was used by the pioneers at the beginning of the 20st century to describe only the radiation-induced adverse tissue reactions related to cell death, a confusion emerged in the literature from the 1930s, as “radiosensitivity” was indifferently used to describe the toxic, cancerous, or aging effect of IR. In parallel, the predisposition to radiation-induced adverse tissue reactions (radiosensitivity), notably observed after radiotherapy appears to be caused by different mechanisms than those linked to predisposition to radiation-induced cancer (radiosusceptibility).
The individual response to ionizing radiation has been the subject of a plethora of studies in the last decades, notably to evaluate the related risks, not only for exposed humans, but also for ecosystems. In particular, the International Commission of Radiation Protection (ICRP) set up in 2018 a dedicated group (TG111) to address the corresponding issues. Unfortunately, while the individual response to radiation is more and more documented, some of its various features are described with non-univocal terms, which does not facilitate their understanding and the elucidation of their intrinsic mechanisms.
This review aims to document these differences in order to better estimate the different radiation-induced risks. It reveals that there are very few syndromes associated with the loss of biological functions involved directly in DNA damage recognition and repair as their role is absolutely necessary for cell viability. By contrast, some cytoplasmic proteins whose functions are independent of genome surveillance may also act as phosphorylation substrates of the ATM protein to regulate the molecular response to IR. Hence, the role of the ATM protein may help classify the genetic syndromes associated with radiosensitivity and/or radiosusceptibility.
2. Historical context
3. Univocal Definitions
the “genomic approach” which consists of inventorying all the genes involved by their expression or polymorphisms in the high throughput studies of radiosensitivity, in order to establish causal links with clinical features . The major advantage of this approach is to get a large number of candidate genes. The major inconvenience is to consider gene expression as a major feature of the response to radiation, while some cases of radiosensitivity are not necessarily linked to a higher or lower gene expression but to protein dysfunction ;
the “clinical approach” which consists of defining the major clinical features of the response to radiation, and thereafter to identify genes in each category. The major advantage of this approach is to gather all the different types of radiation-induced events observed by clinicians. The major inconvenience is to omit some genes that may be involved in the response to radiation while their mutations lead to non-viability and therefore are not associated with any described syndrome .
The radiosensitivity is the proneness to the adverse tissue events that are considered as non-cancer radiation-induced effects and attributable to cell death. Radiosensitivity is generally correlated with unrepaired DNA damage ;
The radiosusceptibility is the proneness to the radiation-induced cancers that are non-toxic radiation-induced effects attributable to cell transformation and genomic instability. Radiosusceptibility is generally correlated with misrepaired DNA damage . As IR is considered as a carcinogenic agent, radiosusceptibility is strongly linked to susceptibility to spontaneous cancers. The term “radiosusceptibility” was proposed through its similarities with “cancer susceptibility”, extensively used in the ICRP reports, and as it introduces the notions of stochastic events ;
The radiodegeneration responses are non-cancer effects attributable to mechanisms related to accelerated aging. Radiodegeneration should be correlated with unrepaired DNA damage that is tolerated by and can cumulate in cells . Radiodegeneration responses cannot be considered similar to radiosensitivity responses as defined above, as their incidence rates, the types of cellular death, and the genes involved are different.
The notions of radiosensitivity, radiosusceptibility, and radiodegeneration appear to be necessary to better describe the different types of individual radiation responses, and permit an evaluation of the specific radiation-induced risks in agreement with clinical observations. This review reveals that there are very few syndromes associated with the loss of biological functions involved directly in DNA damage recognition and repair bas their role is absolutely necessary for cell viability. Interestingly, some cytoplasmic proteins, whose functions are clearly different from genome surveillance, may also act as ATM phosphorylation substrates to regulate the DSB recognition and repair. The radiation-induced ATM nucleoshuttling model may therefore provide a novel approach to classify the genetic syndromes associated with abnormal individual response to radiation, whether linked to toxicity, cancer, or aging.
The entry is from 10.3390/ijms22137158
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