Cell cycle phase is a decisive factor in determining the repair pathway of DNA double-strand breaks (DSBs) by non-homologous end joining (NHEJ) or homologous recombination (HR). Recent experimental studies revealed that 53BP1 and BRCA1 are the key mediators of the DNA damage response (DDR) with antagonizing roles in choosing the appropriate DSB repair pathway in G1, S, and G2 phases. Here, we present a stochastic model of biochemical kinetics involved in detecting and repairing DNA DSBs induced by ionizing radiation during the cell cycle progression. A three-dimensional stochastic process is defined to monitor the cell cycle phase and DSBs repair at times after irradiation. To estimate the model parameters, a Metropolis Monte Carlo method is applied to perform maximum likelihood estimation utilizing the kinetics of γ-H2AX and RAD51 foci formation in G1, S, and G2 phases. The recruitment of DSB repair proteins is verified by comparing our model predictions with the corresponding experimental data on human cells after exposure to X and γ-radiation. Furthermore, the interaction between 53BP1 and BRCA1 is simulated for G1 and S/G2 phases determining the competition between NHEJ and HR pathways in repairing induced DSBs throughout the cell cycle. In accordance with recent biological data, the numerical results demonstrate that the maximum proportion of HR occurs in S phase cells and the high level of NHEJ takes place in G1 and G2 phases. Moreover, the stochastic realizations of the total yield of simple and complex DSBs ligation are compared for G1 and S/G2 damaged cells. Finally, the proposed stochastic model is validated when DSBs induced by different particle radiation such as iron, silicon, oxygen, proton, and carbon.

中文翻译：

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整个细胞周期中 DNA 双链断裂修复的随机模型

细胞周期阶段是决定通过非同源末端连接 (NHEJ) 或同源重组 (HR) 修复 DNA 双链断裂 (DSB) 途径的决定性因素。最近的实验研究表明，53BP1 和 BRCA1 是 DNA 损伤反应 (DDR) 的关键介质，在 G1、S 和 G2 期选择合适的 DSB 修复途径方面具有拮抗作用。在这里，我们提出了一个涉及检测和修复细胞周期进程中电离辐射诱导的 DNA DSB 的生化动力学随机模型。定义了一个三维随机过程来监测细胞周期阶段和辐射后不时的 DSBs 修复。为了估计模型参数，应用 Metropolis Monte Carlo 方法利用 G1、S 和 G2 阶段中 γ-H2AX 和 RAD51 病灶形成的动力学进行最大似然估计。通过将我们的模型预测与暴露于 X 和 γ 辐射后的人体细胞的相应实验数据进行比较，验证了 DSB 修复蛋白的募集。此外，在 G1 和 S/G2 期模拟了 53BP1 和 BRCA1 之间的相互作用，确定了 NHEJ 和 HR 通路在整个细胞周期中修复诱导的 DSB 的竞争。根据最近的生物学数据，数值结果表明，HR 的最大比例发生在 S 期细胞中，而 NHEJ 的高水平发生在 G1 和 G2 期。而且，比较了 G1 和 S/G2 损伤细胞的简单和复杂 DSB 连接总产量的随机实现。最后，当由铁、硅、氧、质子和碳等不同粒子辐射引起 DSB 时，验证了所提出的随机模型。