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

Abstract

Double-strand breaks (DSBs), i.e. the covalent cut of the DNA backbone over both strands, are a detrimental outcome of cell irradiation, bearing chromosomal aberrations and leading to cell apoptosis. In the early stages of the evolution of a DSB, the disruption of the residual interactions between the DNA moieties drives the fracture of the helical layout; in spite of its biological significance, the details of this process are still largely uncertain. Here, we address the mechanical rupture of DNA by DSBs via coarse-grained molecular dynamics simulations: the setup involves a 3855-bp DNA filament and diverse DSB motifs, i.e. within a range of distances between strand breaks (or DSB distance). By employing a coarse-grained model of DNA, we access the molecular details and characteristic timescales of the rupturing process. A sequence-nonspecific, linear correlation is observed between the DSB distance and the internal energy contribution to the disruption of the residual (Watson-Crick and stacking) contacts between DNA moieties, which is seemingly driven by an abrupt, cooperative process. Moreover, we infer an exponential dependence of the characteristic rupture times on the DSB distances, which we associate to an Arrhenius law of thermally-activated processes. This work lays the foundations of a detailed, mechanistic assessment of DSBs in silico, as a benchmark to both numerical simulations and data from single molecule experiments.