Institut d'Electronique, Microélectronique et Nanotechnologie (IEMN, UMR Cnrs 8520), 59652 Villeneuve d'Ascq, France.
Departement de Physique, Université de Lille, 59650 Villeneuve d'Ascq, France.
PLoS Comput Biol. 2018 Jun 14;14(6):e1006224. doi: 10.1371/journal.pcbi.1006224. eCollection 2018 Jun.
Double strand breaks (DSB) in the DNA backbone are the most lethal type of defect induced in the cell nucleus by chemical and radiation treatments of cancer. However, little is known about the outcomes of damage in nucleosomal DNA, and on its effects on damage repair. We performed microsecond-long molecular dynamics computer simulations of nucleosomes including a DSB at various sites, to characterize the early stages of the evolution of this DNA lesion. The damaged structures are studied by the essential dynamics of DNA and histones, and compared to the intact nucleosome, thus exposing key features of the interactions. All DSB configurations tend to remain compact, with only the terminal bases interacting with histone proteins. Umbrella sampling calculations show that broken DNA ends at the DSB must overcome a free-energy barrier to detach from the nucleosome core. Finally, by calculating the covariant mechanical stress, we demonstrate that the coupled bending and torsional stress can force the DSB free ends to open up straight, thus making it accessible to damage signalling proteins.
双链断裂 (DSB) 是癌细胞化学和辐射处理后在细胞核中诱导的最致命的 DNA 缺陷类型。然而，人们对核小体 DNA 损伤的结果以及它对损伤修复的影响知之甚少。我们对包括各种位置 DSB 的核小体进行了微秒长的分子动力学计算机模拟，以表征这种 DNA 损伤的早期演化阶段。通过 DNA 和组蛋白的基本动力学研究受损结构，并与完整的核小体进行比较，从而揭示了相互作用的关键特征。所有 DSB 构型都倾向于保持紧凑，只有末端碱基与组蛋白相互作用。伞状采样计算表明，DSB 处的断裂 DNA 末端必须克服自由能势垒才能从核小体核心中脱离。最后，通过计算协变力学应力，我们证明了耦合的弯曲和扭转应力可以迫使 DSB 自由末端张开，从而使其能够与损伤信号蛋白相互作用。
