Kinetics of radiation-induced DNA double-strand breaks through coarse-grained simulations

Abstract

The DNA lesions enforced by the collision of the radiation field with the cell nucleus involve a variety of local, mostly reversible, mutations of the DNA template. Yet, the double strand break (DSB) of the DNA backbone is reckoned to be the most detrimental outcome of cell irradiation, bearing a non-negligible likelihood of chromosomal aberrations and cell apoptosis from the failure of the DNA damage response (DDR) machinery. In the early stages of the evolution of a DSB lesion, the DNA moieties likely drift from a metastable, bound state, thereby achieving a fracture of the helical layout: arguably, the thermal disruption of the residual interactions at the interface of a DSB lesion drives the rupturing process, despite its kinetics being poorly characterized both in vitro and in silico. Here, we address the characterization of the mechanical fracture of DSB motifs by means of molecular dynamics, employing a coarse-grained DNA model. The setup involves a steered 3855-bp DNA filament, resembling an optical tweezing experiment. Strand breaks are enforced within a range of distances between 0 and 4 base pairs, and the subsequent dislocation of the broken DNA moieties is tracked, accounting for the molecular details and the characteristic timescales of the rupturing process. A linear correlation is observed between the DSB distance (i.e. between strand breaks of the DNA backbone) and the height of the internal energy barrier of the process, separating the bound and fractured states of the DNA filament. Moreover, we infer an exponential dependence of the average fracture times with the DSB distances, thus allowing us to model the DSB event as an activated process following an Arrhenius-Kramers law. This work lays the foundations of a detailed, mechanistic assessment of DSB lesions in silico, as well as of a direct benchmark between numerical simulations and data from single molecule experiments.