Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.
Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.
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DOI：
10.1371/journal.pone.0055190
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Shanley D
中科院分区：
文献类型：
--
作者：
Dolan D;Nelson G;Zupanic A;Smith G;Shanley D
哺乳动物细胞中DNA双链断裂的存在通常激活非同源末端连接（NHEJ）途径以修复损伤并向下游系统发出信号，所述下游系统支配细胞决策，例如凋亡或衰老。信号系统还刺激诸如活性氧（ROS）的产生的效应，其反过来反馈到损伤反应中。虽然NHEJ的整个过程都有很好的记录，但我们对整个系统的动态和如何运作知之甚少。我们已经开发了一个计算模型，其中包括DNA蛋白激酶（DNA-PK）依赖的NHEJ（D-NHEJ）和备份NHEJ机制（B-NHEJ），并使用它来解释的动态响应不同水平的γ射线照射诱导的损伤在人成纤维细胞。我们的工作表明，观察到的转变从快速到缓慢修复的DNA损伤灶在更高水平的损害不能被解释仅仅由内在的随机性在NHEJ系统。相反，我们的模型强调了Ku氧化的重要性，这导致Ku从DNA损伤灶的解离速率增加，并使修复有利于效率较低的B-NHEJ系统。
The presence of DNA double-stranded breaks in a mammalian cell typically activates the Non-Homologous End Joining (NHEJ) pathway to repair the damage and signal to downstream systems that govern cellular decisions such as apoptosis or senescence. The signalling system also stimulates effects such as the generation of reactive oxygen species (ROS) which in turn feed back into the damage response. Although the overall process of NHEJ is well documented, we know little of the dynamics and how the system operates as a whole. We have developed a computational model which includes DNA Protein Kinase (DNA-PK) dependent NHEJ (D-NHEJ) and back-up NHEJ mechanisms (B-NHEJ) and use it to explain the dynamic response to damage induced by different levels of gamma irradiation in human fibroblasts. Our work suggests that the observed shift from fast to slow repair of DNA damage foci at higher levels of damage cannot be explained solely by inherent stochasticity in the NHEJ system. Instead, our model highlights the importance of Ku oxidation which leads to increased Ku dissociation rates from DNA damage foci and shifts repair in favour of the less efficient B-NHEJ system.
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DOI：
10.1073/pnas.95.2.525
发表时间：
1998-01-20
影响因子：
11.1
作者：
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