Modeling a biological process equips us with more comprehensive insight into the process and a more advantageous experimental design. Non-homologous end joining (NHEJ) is a major double-strand break (DSB) repair pathway that occurs throughout the cell cycle. The objective of the current work is to model the fast and slow phases of NHEJ in G1 phase of the cell cycle following exposure to ionizing radiation (IR). The fast phase contains the major components of NHEJ; Ku70/80 complex, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and XLF/XRCC4/ligase IV complex (XXL). The slow phase in G1 phase of the cell cycle is associated with more complex lesions and involves ATM and Artemis proteins in addition to the major components. Parameters are mainly obtained from experimental data. The model is successful in predicting the kinetics of DSB foci in 13 normal, ATM-deficient, and Artemis-deficient mammalian fibroblast cell lines in G1 phase of the cell cycle after exposure to low doses of IR. The involvement of ATM provides the model with the potency to be connected to different signaling pathways. Ku70/80 concentration and DNA-binding rate as well as XXL concentration and enzymatic activity are introduced as the best targets for affecting NHEJ DSB repair process. On the basis of the current model, decreasing concentration and DNA binding rate of DNA-PKcs is more effective than inhibiting its activity towards the Artemis protein.

中文翻译：

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模拟 DNA-PK、Artemis 和 ATM 在细胞周期 G1 期非同源末端连接修复中的相互作用

对生物过程建模使我们能够更全面地了解该过程和更有利的实验设计。非同源末端连接 (NHEJ) 是一种主要的双链断裂 (DSB) 修复途径，发生在整个细胞周期中。当前工作的目标是模拟细胞周期 G1 期暴露于电离辐射 (IR) 后 NHEJ 的快速和慢速阶段。快速阶段包含 NHEJ 的主要成分；Ku70/80 复合物、DNA 依赖性蛋白激酶催化亚基 (DNA-PKcs) 和 XLF/XRCC4/连接酶 IV 复合物 (XXL)。细胞周期 G1 期的缓慢期与更复杂的病变有关，除主要成分外，还涉及 ATM 和 Artemis 蛋白。参数主要来自实验数据。该模型成功地预测了暴露于低剂量 IR 后细胞周期 G1 期的 13 种正常、ATM 缺陷和 Artemis 缺陷哺乳动物成纤维细胞系中 DSB 病灶的动力学。ATM 的参与为模型提供了连接不同信号通路的能力。Ku70/80 浓度和 DNA 结合率以及 XXL 浓度和酶活性被引入作为影响 NHEJ DSB 修复过程的最佳目标。在当前模型的基础上，降低 DNA-PKcs 的浓度和 DNA 结合率比抑制其对 Artemis 蛋白的活性更有效。ATM 的参与为模型提供了连接不同信号通路的能力。Ku70/80 浓度和 DNA 结合率以及 XXL 浓度和酶活性被引入作为影响 NHEJ DSB 修复过程的最佳目标。在当前模型的基础上，降低 DNA-PKcs 的浓度和 DNA 结合率比抑制其对 Artemis 蛋白的活性更有效。ATM 的参与为模型提供了连接不同信号通路的能力。Ku70/80 浓度和 DNA 结合率以及 XXL 浓度和酶活性被引入作为影响 NHEJ DSB 修复过程的最佳目标。在当前模型的基础上，降低 DNA-PKcs 的浓度和 DNA 结合率比抑制其对 Artemis 蛋白的活性更有效。