不同的计算机模型假设对 DNA 损伤和修复预测的影响。

Effects of Differing Underlying Assumptions in In Silico Models on Predictions of DNA Damage and Repair.

机构信息

Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom.

The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.

出版信息

Radiat Res. 2023 Dec 1;200(6):509-522. doi: 10.1667/RADE-21-00147.1.

Abstract

The induction and repair of DNA double-strand breaks (DSBs) are critical factors in the treatment of cancer by radiotherapy. To investigate the relationship between incident radiation and cell death through DSB induction many in silico models have been developed. These models produce and use custom formats of data, specific to the investigative aims of the researchers, and often focus on particular pairings of damage and repair models. In this work we use a standard format for reporting DNA damage to evaluate combinations of different, independently developed, models. We demonstrate the capacity of such inter-comparison to determine the sensitivity of models to both known and implicit assumptions. Specifically, we report on the impact of differences in assumptions regarding patterns of DNA damage induction on predicted initial DSB yield, and the subsequent effects this has on derived DNA repair models. The observed differences highlight the importance of considering initial DNA damage on the scale of nanometres rather than micrometres. We show that the differences in DNA damage models result in subsequent repair models assuming significantly different rates of random DSB end diffusion to compensate. This in turn leads to disagreement on the mechanisms responsible for different biological endpoints, particularly when different damage and repair models are combined, demonstrating the importance of inter-model comparisons to explore underlying model assumptions.

摘要

通过放射疗法治疗癌症的关键因素是诱导和修复 DNA 双链断裂(DSB)。为了通过 DSB 诱导来研究辐射事件与细胞死亡之间的关系,已经开发了许多计算模型。这些模型生成并使用了针对研究人员调查目标的自定义数据格式,并且通常侧重于特定的损伤和修复模型配对。在这项工作中,我们使用报告 DNA 损伤的标准格式来评估不同的、独立开发的模型的组合。我们证明了这种比较的能力可以确定模型对已知和隐含假设的敏感性。具体来说,我们报告了关于 DNA 损伤诱导模式的假设差异对预测初始 DSB 产率的影响,以及随后对衍生 DNA 修复模型的影响。观察到的差异强调了在纳米尺度上考虑初始 DNA 损伤而不是微米尺度上的重要性。我们表明,DNA 损伤模型的差异导致随后的修复模型假设随机 DSB 末端扩散的补偿速率明显不同。这反过来又导致对不同生物学终点负责的机制产生分歧,尤其是当不同的损伤和修复模型结合使用时,这表明进行模型间比较以探索基础模型假设的重要性。

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