DNA break clustering inside repair domains predicts cell death and mutation frequency in human fibroblasts and in Chinese hamster cells for a 10^3x range of linear energy transfers

Abstract

Cosmic radiation, composed of high charged and energy (HZE) particles, causes cell death and mutations that can subsequently lead to cancers. Radiation-mediated mutations are induced by inter- and intra-chromosomal rearrangements (translocations, deletions, inversions) that are triggered by misrepaired DNA breaks, especially double-strand breaks (DSBs). In this work, we introduce a new model to predict radiation-mediated induction of cell death and mutation in two different cell lines across a large range of linear energy transfer (LET) values, based on the assumption that DSBs cluster into repair domains, as previously suggested by our group. Specifically, we propose that the probabilities of cell survival and cell mutation can be determined from the number of DSBs and the number of pairwise DSB interactions forming radiation-induced foci. We computed the distribution and locations of DSBs with the new simulation code RITCARD (relativistic ion tracks, chromosome aberrations, repair, and damage) and combined them with experimental data from HF19 human fibroblasts and V79 Chinese hamster cells to derive the parameters of our model and expand its predictions to the relative biological effectiveness (RBE) for cell survival and mutation in both cell lines in response to 9 different irradiation particles and energies ranging from 10 to 1,600 MeV/n. Our model generates the correct bell shape of LET dependence for RBE, as well as similar RBE values as experimental data, notably including data that were not used to set the model parameters. Interestingly, our results also suggest that cell orientation (parallel or perpendicular) with respect to the HZE beam can modulate the RBE for both cell death and mutation frequency. Cell orientation effects, if confirmed experimentally, would be another strong piece of evidence for the existence of DNA repair domains and their critical role in interpreting cellular sensitivity to cosmic radiation and hadron therapy. AUTHOR SUMMARYOne of the main hazards of human spaceflight beyond low Earth orbit is space radiation exposure. Galactic cosmic rays (GCRs), in particular their high-charge and high-energy particle component, induce a unique spatial distribution of DNA double strand breaks in the nucleus along their traversal in the cell [1], which result in significantly higher cancer risk than X-rays [2]. To mitigate this hazard, there is a significant need to better understand and predict the effects of cosmic radiation exposure at the cellular level. We have computationally predicted two biological endpoints - cell survival and probability of mutations, critical for cancer induction mechanisms - for the full spectrum of cosmic radiation types and energies, by modeling the distribution of DNA damage locations within the cell nucleus. From experimental results of cell survival and mutation probability in two standard cell lines, we were able to derive the parameters of the model for multiple radiation qualities, both biological endpoints, and two irradiation orientations. The model was validated against biological data and showed high predictive capability on data not used for tuning the model. Overall, this work opens new perspectives to predict multiple responses to cosmic radiation, even with limited experimental data available.