A biphasic spatiotemporal non-homologous end joining model coupled with Monte Carlo DNA damage data for chromosome aberration prediction

Abstract Objective. This study extends a DNA damage simulation package to incorporate a biphasic spatiotemporal non-homologous end joining (NHEJ) repair framework. The aim is to predict radiation induced chromosome aberrations for various beam qualities and dose rates from an independent parameter set. Approach. A biphasic NHEJ kinetic model, characterized by fast and slow components with experimentally constrained repair rate constants ( λ f = 2.48 h −1 and λ s = 0.408 h −1 ) and slow portion ( η DSB = 19%), was coupled to a DNA end diffusion process ( D = 0.1 μm 2 h −1 ). DNA damage data from Monte Carlo-based biophysical program was used as input, while different types of chromosome aberrations were generated as output. The extended framework was benchmarked against chromosome aberration measurements in human fibroblasts under acute γ -rays, α particles, and chronic low dose-rate γ -ray irradiations. All parameters were obtained from independent measurements without fitting to chromosome aberration data. Model performance was evaluated using the coefficient of determination ( R 2 ). Main Results. For acute γ -rays and α particles, the proposed model reproduced the dose-response curves of dicentrics and interstitial deletions with reasonable accuracy, while larger deviations were observed for rings and terminal deletions. The corresponding total-aberration R 2 were 0.973 and 0.947. Notably, the inclusion of spatiotemporal repair dynamics substantially improved agreement of rings and terminal deletions for α -particles compared to a pure distance-dependent model. Simulations of chronic γ -ray irradiations reproduced total aberration yields at 6.3 cGy h −1 with R 2 = 0.968, while the 2.8 cGy h −1 case exhibited notable deviation with R 2 = − 0.517. Sensitivity analyses suggested model stability and robustness with all sensitivity coefficients remaining below 1.3. Significance. By integrating spatial diffusion and biphasic repair kinetics, the proposed model provides a quantitative link between microdosimetric energy deposition and macroscopic chromosome aberrations. The approach offers a foundation for mechanistic modeling of relative biological effectiveness in particle therapy.