Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Radiation Protection, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
Mutat Res. 2013 Aug 30;756(1-2):213-23. doi: 10.1016/j.mrgentox.2013.06.013. Epub 2013 Jun 28.
A computational model of radiation-induced chromosome aberrations in human cells within the PARTRAC Monte Carlo simulation framework is presented. The model starts from radiation-induced DNA damage assessed by overlapping radiation track structures with multi-scale DNA and chromatin models, ranging from DNA double-helix in atomic resolution to chromatin fibre loops, heterochromatic and euchromatic regions, and chromosome territories. The repair of DNA double-strand breaks via non-homologous end-joining is followed. Initial spatial distribution and complexity, diffusive motion, enzymatic processing, synapsis and ligation of individual DNA ends from the breaks are simulated. To enable scoring of different chromosome aberration types resulting from improper joining of DNA fragments, the repair module has been complemented by tracking the chromosome origin of the ligated fragments and the positions of centromeres. The modelled motion of DNA ends has sub-diffusive characteristics and corresponds to measured chromatin mobility within time-scales of a few hours. The calculated formation of dicentrics after photon and α-particle irradiation in human fibroblasts is compared to experimental data (Cornforth et al., 2002, Radiat Res 158, 43). The predicted yields of dicentrics overestimate the measurements by factors of five for γ-rays and two for α-particle irradiation. Nevertheless, the observed relative dependence on radiation dose is correctly reproduced. Calculated yields and size distributions of other aberration types are discussed. The present work represents a first mechanistic approach to chromosome aberrations and their kinetics, combining full track structure simulations with detailed models of chromatin and accounting for the kinetics of DNA repair.
提出了一种在 PARTRAC 蒙特卡罗模拟框架内用于模拟人类细胞中辐射诱导的染色体畸变的计算模型。该模型从通过重叠辐射轨迹结构与多尺度 DNA 和染色质模型评估的辐射诱导的 DNA 损伤开始，范围从原子分辨率的 DNA 双螺旋到染色质纤维环、异染色质和常染色质区域以及染色体区域。随后通过非同源末端连接修复 DNA 双链断裂。模拟了单个 DNA 末端的初始空间分布和复杂性、扩散运动、酶处理、来自断裂处的断裂处的突触和连接。为了能够对由于 DNA 片段不正确连接而导致的不同类型的染色体畸变进行评分，修复模块通过跟踪连接片段的染色体起源和着丝粒的位置得到了补充。模拟的 DNA 末端运动具有亚扩散特征，并且对应于在几小时的时间尺度内测量到的染色质流动性。与实验数据（Cornforth 等人，2002 年，Radiat Res 158, 43）相比，计算了人成纤维细胞中光子和α粒子照射后双着丝粒的形成。γ射线照射后双着丝粒的预测产率比测量值高估了五倍，而α-粒子照射后的预测产率比测量值高估了两倍。尽管如此，仍然正确再现了观察到的对辐射剂量的相对依赖性。讨论了其他畸变类型的计算产率和尺寸分布。目前的工作代表了一种用于染色体畸变及其动力学的第一个机制方法，它结合了完整的轨迹结构模拟和染色质的详细模型，并考虑了 DNA 修复的动力学。
