What Does the History of Research on the Repair of DNA Double-Strand Breaks Tell Us?—A Comprehensive Review of Human Radiosensitivity

Abstract

Our understanding of the molecular and cellular response to ionizing radiation (IR) has progressed considerably. This is notably the case for the repair and signaling of DNA double-strand breaks (DSB) that, if unrepaired, can result in cell lethality, or if misrepaired, can cause cancer. However, through the different protocols, techniques, and cellular models used during the last four decades, the DSB repair kinetics and the relationship between cellular radiosensitivity and unrepaired DSB has varied drastically, moving from all-or-none phenomena to very complex mechanistic models. To date, personalized medicine has required a reliable evaluation of the IR-induced risks that have become a medical, scientific, and societal issue. However, the molecular bases of the individual response to IR are still unclear: there is a gap between the moderate radiosensitivity frequently observed in clinic but poorly investigated in the publications and the hyper-radiosensitivity of rare but well-characterized genetic diseases frequently cited in the mechanistic models. This paper makes a comprehensive review of semantic issues, correlations between cellular radiosensitivity and unrepaired DSB, shapes of DSB repair curves, and DSB repair biomarkers in order to propose a new vision of the individual response to IR that would be more coherent with clinical reality.

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

“…Nevertheless, NHEJ is supposed to be predominant in mammalian cells compared with microorganisms 164,165 . Since the term homologous was used previously in the HR pathway by radiobiological community, the second discovered pathway was defined as NHEJ 166,167 . However, some radiobiologists disagree with the naming approach and have suggested the existence of other DSB repair pathways because studies have revealed that in cancer cells with extreme radiotherapy sensitivity, both the HR and NHEJ pathways exist, suggesting that other repair pathways may also be functioning 168 .…”

DNA Double-Strand Breaks Induced in Human Cells by Twelve Metallic Species: Quantitative Inter-Comparisons and Influence of the ATM Protein

“…In quiescent mammalian cells, the DSB recognition and repair is mainly ensured by the predominant non-homologous end-joining (NHEJ) pathway whose phosphorylation of variant H2AX histone proteins (γH2AX) is the earliest sensor [23]. Recently, the rate of RI nucleo-shuttling of the ATM protein (RIANS), a major actor of DSB repair and signalling, was found to be a reliable predictor of radiosensitivity and cellular toxicity [24][25][26][27][28][29][30]. The following mechanistic model was proposed: RI oxidization triggers the monomerization of the cytoplasmic ATM dimers, which allows the ATM monomers to diffuse in the nucleus.…”

“…The following mechanistic model was proposed: RI oxidization triggers the monomerization of the cytoplasmic ATM dimers, which allows the ATM monomers to diffuse in the nucleus. Once in the nucleus, the ATM monomers phosphorylate H2AX histones, which triggers the formation of nuclear γH2AX foci and DSB recognition and repair by NHEJ [24,[29][30][31]. A delay in the RIANS may be caused by an overproduction of some ATM phosphorylation substrate proteins in the cytoplasm that sequestrate the ATM monomers.…”

Impaired DNA Repair Fidelity in a Breast Cancer Patient With Adverse Reactions to Radiotherapy

“…Many reports about cohorts and individual cases of radiosensitivity have been published where clinical radiosensitivity was associated with certain in vitro experimental endpoints with variable results ( 14 ). Between the various mechanistic pathways investigated, the radiation-induced DNA damage response remains the most well-characterized ( 32 , 33 ). However, some other mechanisms and pathways were suggested to be involved in patient radiosensitivity, including oxidative stress, stem cell response, activation of inflammation pathways with the secretion of cytokines, genetics, non-coding RNA, and potentially epigenetic factors that can be studied using a large number of functional assays ( 3 ).…”