AnIn SilicoModel of DNA Repair for Investigation of Mechanisms in Non-Homologous End Joining

Abstract

In human cells, non-homologous end joining is the preferred process to repair radiation induced DNA double strand breaks. The complex nature of such biological systems involves many individual actions that combine to produce an overall behaviour. As such, experimentally determining the mechanisms involved, their individual roles, and how they interact is challenging. An in silico approach to radiobiology is uniquely suited for detailed exploration of these complex interactions and the unknown effects of specific mechanisms on overall behaviour. We detail the construction of a mechanistic model by combination of several, experimentally supported, hypothesised mechanisms.Compatibility of these mechanisms was tested by fitting to results reported in the literature. To avoid over fitting, individual mechanisms within this pathway were sequentially fitted. We demonstrate that using this approach the model is capable of reproducing published protein kinetics and overall repair trends. This process highlighted specific biological mechanisms which are not clearly defined experimentally, and showed that the assumed motion of individual double strand break ends plays a crucial role in determining overall system behaviour.

Ionizing Radiation and Complex DNA Damage: Quantifying the Radiobiological Damage Using Monte Carlo Simulations

“…In a very preliminary study, Warmenhoven et al [155,156] investigated, using simulation tools, the mechanisms in NHEJ. They developed a model that takes into account several mechanisms that are experimentally supported and were incorporated into a theory of sequential joining, to finally reproduce experimental results that are reported in the literature.…”

Clinically relevant nanodosimetric simulation of DNA damage complexity from photons and protons

“…We do not assign toxicities to the types of breaks predicted, since we don't include a model of DNA repair, though this work is ongoing. 82 When comparing the predicted induction of complex breaks between protons and photons the RBE Complex increases from 0.95, at the entrance, to 1.47 at the distal edge (ESI 3 †). These trends are largely consistent with some of the predictions made by phenomenological models of RBE for cell kill.…”

Development of a coupled simulation toolkit for computational radiation biology based on Geant4 and CompuCell3D

“…In future study, we can model the cellular response for molecular concentrations that can steer the behaviors of biological cells by modulating their biochemical machinery. For example, we can incorporate the repair pathways, such as NHEJ and Homologous Recombination, by applying the well-known models (Warmenhoven et al 2018, Ingram et al 2019 about DNA damage repair using the intracellular simulation functionality of CC3D. Oxygen is an important factor moderating cellular radiation response.…”