Dynamical insights on the role of supercoiling on DNA radiosensitivity

Objective. Ionizing radiation is a major source of biological hazard, bearing a broad range of detrimental lesions of the DNA structural and molecular integrity-often leading to genomic instabilities and severe cellular outcomes. The sensitivity of the DNA molecule to ionizing radiation is deeply affected by a variety of chemical and biophysical factors controlling its dynamical behavior, as well as by diverse cellular processes and response pathways. With the available literature offering no clear-cut, conclusive perspective, this work aims at characterizing the role of supercoiling in modulating the mechanical response of DNA to double strand breaks, and discuss the outcome within the broader framework of DNA radiosensitivity.Approach. We assess the linearization of a supercoiled 672-bp DNA minicircle by double strand breaks, i.e. the disruption of the covalent DNA backbone on both complementary strands of the double helix, which is a fingerprint lesion of ionizing radiation. To this effect, we employ classical coarse-grained molecular dynamics simulations, and verify how the sequence and supercoiling regime of the minicircle affect the kinetics of the rupturing process.Main results. We observe that the excess torsional stress overall enhances the likelihood of the DNA rupturing but in one specific scenario-associated with a biologically-significant level of negative superhelical density-thereby highlighting a strongly non-symmetric behavior between positive and negative supercoiling regimes.Significance. This work deals critical dynamical insights on the role of topology in the mechanical response of DNA to double strand breaks: together with the decrease of the effective volume of a DNA target enforced by an excess/defect of superhelical density, we infer that a degree of supercoiling belonging to an average biological scenario might factor in the earliest radiobiological response of (naked) DNA.