Stochastic Simulation of DNA Double-Strand Break Repair by Non-homologous End Joining Based on Track Structure Calculations
Stochastic Simulation of DNA Double-Strand Break Repair by Non-homologous End Joining Based on Track Structure Calculations
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DOI：
10.1667/rr1965.1
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发表时间：
2010-05-01
影响因子：
3.4
通讯作者：
Kundrat, Pavel
中科院分区：
文献类型：
--
作者：
Friedland, Werner;Jacob, Peter;Kundrat, Pavel
建立了非同源末端连接途径DNA修复的蒙特卡罗模拟模型。由蒙特卡罗轨道结构代码PARTRAC计算的初始DNA损伤提供了有关双链断裂（dsb）空间分布和损伤复杂性表征的起始条件。DNA末端经历修复酶的附着和解离，描述为随机一阶动力学以及考虑核附着位点的逐步扩散运动。带有DNA- pk的DNA末端在空间接近条件下进入突触。在突触后，假设对干净的DNA端采用单一的速率限制步骤，对脏的DNA端考虑逐步去除附近的碱基损伤和链断裂。建立了四种简单的模型情景，反映了对DSB修复慢期起源的不同假设。突触前期的参数来源于Ku70/Ku80和DNA-PK结合和解离动力学的实验数据。（137）Cs γ辐照后人成纤维细胞的突触后期时间常数已适应于实验DSB再连接动力学。除了DSB再连接动力学外，还确定了残余DSB、错误再连接DSB和染色体畸变的产率作为剂量的函数，并与实验数据进行了比较。三种模型情景明显高估了低剂量照射后长期修复后的残余dsb，而错误重新连接的dsb和染色体畸变与测量结果惊人地吻合。(C) 2010年由辐射研究学会出版
A Monte Carlo simulation model for DNA repair via the non-homologous end-joining pathway has been developed. Initial DNA damage calculated by the Monte Carlo track structure code PARTRAC provides starting conditions concerning spatial distribution of double-strand breaks (DSBs) and characterization of lesion complexity. DNA termini undergo attachment and dissociation of repair enzymes described in stochastic first-order kinetics as well as step-by-step diffusive motion considering nuclear attachment sites. Pairs of DNA termini with attached DNA-PK enter synapsis under spatial proximity conditions. After synapsis, a single rate-limiting step is assumed for clean DNA ends, and step-by-step removal of nearby base lesions and strand breaks is considered for dirty DNA ends. Four simple model scenarios reflecting different hypotheses on the origin of the slow phase of DSB repair have been set up. Parameters for the presynaptic phase have been derived from experimental data for Ku70/Ku80 and DNA-PK association and dissociation kinetics. Time constants for the post-synaptic phase have been adapted to experimental DSB rejoining kinetics for human fibroblasts after (137)Cs gamma irradiation. In addition to DSB rejoining kinetics, the yields of residual DSBs, incorrectly rejoined DSBs, and chromosomal aberrations have been determined as a function of dose and compared with experimental data. Three of the model scenarios obviously overestimate residual DSBs after long-term repair after low-dose irradiation, whereas misrejoined DSBs and chromosomal aberrations are in surprisingly good agreement with measurements. (C) 2010 by Radiation Research Society