A Multiscale Kinetic Model of DNA Damage Signalling and Repair under Combined Proton and Nanoparticle Exposure

Abstract

We present a multiscale kinetic framework for predicting the induction, processing, and biological consequences of DNA double-strand breaks (DSBs) in AG1522 human fibroblasts exposed to combined proton and 15-nm GNP irradiation. The model connects proton dose and linear energy transfer (LET), perinuclear GNP localization, secondary-electron and reactive-species production, and Poisson--Gamma-distributed lesion induction. Initial DSBs are separated into simple and complex classes and coupled to an ATM--$γ$H2AX--53BP1 signalling cascade, cell-cycle-dependent allocation among canonical non-homologous end joining, homologous recombination, alternative end joining, and single-strand annealing, and class-specific repair fidelities. The model identifies the initial complex-lesion fraction and its slower resolution, rather than post-irradiation conversion of simple DSBs, as the principal determinants of persistent damage under high-LET, GNP-enhanced irradiation. The residual-DSB results provide strong internal out-of-sample validation of the kinetic component. However, the opposing biases in correct repair and misrepair reveal an inconsistency between the class-specific fidelities and the supplied integrated-fidelity endpoint. These repair-fate predictions should therefore be regarded as model-constrained estimates pending independent measurements of correct-end joining, mutation, chromosome aberrations, and clonogenic survival.