After radiation exposure, one of the critical processes for cellular survival is the repair of DNA double strand breaks. The pathways involved in this response are complex in nature and involve many individual steps that act across different time scales, all of which combine to produce an overall behaviour. It is therefore experimentally challenging to unambiguously determine the mechanisms involved and how they interact whilst maintaining strict control of all confounding variables. In silico methods can provide further insight into results produced by focused experimental investigations through testing of the hypotheses generated. Such computational testing can asses competing hypotheses by investigating their effects across all time scales concurrently, highlighting areas where further experimental work can have the most significance. We describe the construction of a mechanistic model by combination of several hypothesised mechanisms reported in the literature and supported by experiment. Compatibility of these mechanisms was tested by fitting simulation to results reported in the literature. To avoid over-fitting, we used an approach of sequentially testing individual mechanisms within this pathway. We demonstrate that using this approach the model is capable of reproducing published protein kinetics and overall repair trends. This provides evidence supporting the feasibility of the proposed mechanisms and revealed how they interact to produce an overall behaviour. Furthermore, we show that the assumed motion of individual double strand break ends plays a crucial role in determining overall system behaviour.

中文翻译：

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机械计算机模拟提供了对非同源末端连接途径和双链断裂末端移动性的见解。

辐射暴露后，细胞存活的关键过程之一是DNA双链断裂的修复。这种响应所涉及的途径本质上是复杂的，涉及许多跨不同时间尺度起作用的单独步骤，所有这些步骤组合在一起就产生了整体行为。因此，在保持对所有混杂变量的严格控制的同时，明确确定所涉及的机制及其相互作用方式在实验上具有挑战性。电子计算机方法可以通过测试生成的假设，进一步深入研究重点实验研究产生的结果。这样的计算测试可以通过同时调查所有时间范围内的影响来评估竞争假设，从而突出显示进一步的实验工作可能最重要的领域。我们通过文献中报道并由实验支持的几种假设机制的组合来描述机械模型的构建。通过对文献报道的结果进行模拟拟合，测试了这些机制的兼容性。为了避免过度拟合，我们使用了一种方法来顺序测试此路径内的各个机制。我们证明，使用这种方法，该模型能够复制已发布的蛋白质动力学和整体修复趋势。这提供了支持所提出机制可行性的证据，并揭示了它们如何相互作用以产生整体行为。此外，我们表明，单个双链断裂末端的假定运动在确定总体系统行为中起着至关重要的作用。