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.
Highlights
The statement that radiation-induced damage inside the cell nucleus are the key-elements of the individual response to ionizing radiation (IR) is much anterior to the discovery of the DNA structure itself
Since radiation-induced chromosome breaks may be generated by the propagation of radiation-induced DNA breaks throughout the cell cycle, cytogenetics research has been associated with DNA repair research since the discovery of the DNA structure in the 1950s
This paper provides a comprehensive review of individual radiosensitivity and radiation-induced double-strand breaks (DSB) repair and signaling all along the history for radiation research
Summary
The statement that radiation-induced damage inside the cell nucleus are the key-elements of the individual response to ionizing radiation (IR) is much anterior to the discovery of the DNA structure itself. Further investigations up to 24 h post-irradiation showed that AT cells repaired nearly 90% of the radiation-induced DSB Their SF2 was similar to the most hyper-radiosensitive rodent cell lines [22] (Figure 2B). The fibroblasts derived from this patient showed cellular radiosensitivity and DSB repair data similar to those of the CHO-xrs-5 and xrs-6 cell lines (Figure 2C). .EEvvoolluuttiioonn oofftthheeiinntteerrpprreettaattiioonn ooff tthhee DDSSBB rreeppaaiirr ccuurrvveess. By adding an extra-complexity to our vision of DSB repair, the A-NHEJ pathway is not necessarily equivalent to the B-NHEJ pathway evoked above, while C-NHEJ is likely to be DNA-PK- and LIG4-dependent and refers to D-NHEJ All these investigations and hypotheses converge toward the same conclusion: in addition to the NHEJ and the HR, an alternative DSB repair pathway should exist, be active in G0/G1 cells, and be responsible for genomic instability and cancer proneness (Figure 1). A question remains: how should we further investigate the different DSB repair pathways? (Figure 4)
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