Influence of Individual Radiosensitivity on the Adaptive Response Phenomenon: Toward a Mechanistic Explanation Based on the Nucleo-Shuttling of ATM Protein

摘要

The adaptive response (AR) phenomenon generally describes a protective effect caused by a “priming” low dose (d_AR) delivered after a period of time (Δt_AR) before a higher “challenging” dose (D_AR). The AR is currently observed in human cells if d_AR, Δt_AR, and D_AR belong to (0.001-0.5 Gy), (2-24 hours), (0.1-5 Gy), respectively. In order to investigate the molecular mechanisms specific to AR in human cells, we have systematically reviewed the experimental AR protocols, the cellular models, and the biological endpoints used from the 1980s. The AR appears to be preferentially observed in radiosensitive cells and is strongly dependent on individual radiosensitivity. To date, the model of the nucleo-shuttling of the ATM protein provides a relevant mechanistic explanation of the AR molecular and cellular events. Indeed, the priming dose d_AR may result in the diffusion of a significant amount of active ATM monomers in the nucleus. These ATM monomers, added to those induced directly by the challenging dose D_AR, may increase the efficiency of the response to D_AR by a better ATM-dependent DNA damage recognition. Such mechanistic model would also explain why AR is not observed in radioresistant or hyperradiosensitive cells. Further investigations at low dose are needed to consolidate our hypotheses.