Dynamical insights on the role of supercoiling on DNA radiosensitivity

Ionizing radiation (IR) is a major source of biological hazard, associated with a broad range of detrimental lesions of the structural and molecular integrity of the DNA molecule--often leading to genomic instabilities and severe cellular outcomes. The radiosensitivity of DNA is deeply affected by a variety of chemical and biophysical factors, which control the dynamical behavior of the molecule as well as diverse cellular processes and response pathways. Among these factors, the role of supercoiling in modulating DNA radiosensitivity remains controversial, with the existing literature being inconclusive on its effective contribution. Here, we characterize the linearization of a supercoiled DNA minicircle by double-strand breaks (i.e., the rupture of the covalent DNA backbone on both complementary strands of the double helix) via classical coarse-grained molecular dynamics simulations, and verify how the initial supercoiling regime of the molecule influences the kinetics of the rupturing process. We observe that the excess torsional stress overall enhances the rupturing likelihood but in one specific scenario--associated with a biologically-significant level of (negative) superhelical density: This effect highlights a strong asymmetry between positive and negative supercoiling regimes and provides critical insights on the role of topology on the radiosensitivity of DNA molecules.