Correlation Between DNA Double-Strand Break Distribution in 3D Genome and Radiation-Induced Cell Death

Abstract

The target theory is the most classical hypothesis explaining radiation-induced cell death, the physical or biological nature of the "target" remains ambiguous. This study hypothesizes that the distribution of DNA double-strand breaks (DSBs) within the 3D genome is a pivotal factor affecting the probability of radiation-induced cell death. We propose that clustered DSBs in DNA segments with high interaction frequencies are more susceptible to leading to cell death than isolated DSBs. Topologically associating domains (TAD) can be regarded as the reference unit for evaluating the impact of DSB clustering in the 3D genome. To quantify this correlation between the DSB distribution in 3D genome and radiation-induced effect, we developed a simplified model considering the DSB distribution across TADs. Utilizing track-structure Monte Carlo codes to simulate the electron and carbon ion irradiation, we calculated the incidence of each case across a variety of radiation doses and LETs. Our simulation results indicate that DSBs in TADs with frequent interactions (case 3) are significantly more likely to induce cell death than clustered DSBs within a single TAD (case 2). Moreover, case 2 is significantly more likely to induce cell death than isolated DSBs (case 1). The curves of the incidence of case 2 and case 3 versus LETs have a similar shape to the radiation quality factor used in radiation protection. This indicates that these two cases are also associated with the stochastic effects induced by high LET irradiation. Our study underscores the significance of the 3D genome structure in the fundamental mechanisms of radiobiological effects. The hypothesis in our research offers novel perspectives on the mechanisms that regulate radiobiological effects. Moreover, it serves as a valuable reference for establishing mechanistic models that can predict cell survival under different doses and LETs.