Computer Modeling of DNA Double-Strand Break Repair (pilot)

双链断裂(DSB)是对细胞最危险的DMA损伤形式。当DSB被 如果没有得到很好的修复，它们会导致染色体异常(即基因组的大规模重排)。 染色体异常是外源性和内源性DMA损伤剂的特征(例如， 代谢反应、不完全重组事件、辐射、某些化学物质产生的自由基) 并且经常与癌症的发生和发展有关。其中一个 真核细胞对DSB诱导的最早反应是组蛋白H_2AX的磷酸化 断裂附近的分子(用y-H_2AX表示)。修饰的组蛋白y-H_2AX对 高效的DSB识别和处理，据信它在招聘和 组装DMA维修机械。与这些观察结果一致的是，细胞缺乏H2AX 磷酸化表现为基因组不稳定、肿瘤易感性和辐射过敏。的目标是 该项目旨在开发一种定量模型，以帮助确定组蛋白y-H_2AX在 DNA修复蛋白在DSB上的募集过程。我们将通过首先开发一种 DSB前染色质相关蛋白在细胞核内扩散的计算模型 归纳法。这将有助于我们估计正常情况下的扩散参数和蛋白质浓度。 条件。其次，我们将估计扩散特性和蛋白质浓度如何偏离 在诱发DSB后的先前估计值。这些结果将使我们能够表征 不同的募集模型并定量鉴定γ-H_2AX在蛋白质募集中的作用 DSB诱导。该项目将与实验生物学家密切合作开发。 与公共卫生的相关性：修复/错误修复反应的量化对于进一步 了解染色体异常形成的过程，如在致癌过程中观察到的过程 和癌症进展，以及在暴露于DMA破坏剂之后。既然我们感兴趣的是 我们的研究将有助于更好地预测辐射敏感性和癌症 环境或职业暴露的风险，估计过去的辐射暴露，以及 提高肿瘤放射治疗水平。

Double Strand Breaks (DSBs) are the most dangerous form of DMA damage for the cell. When DSBs are not faithfully repaired they introduce chromosome aberrations (i.e. large rearrangement of the genome). Chromosome aberrations are the signature of exogenous and endogenous DMA damaging agents (e.g., free radicals from metabolic reactions, incomplete recombination events, radiation, certain chemicals) and are frequently associated with processes of carcinogenesis and cancer progression. One of the earliest responses of the eukaryotic cell to the induction of DSBs is the phosphorylation of histone H2AX molecules (denoted by y -H2AX) in the vicinity of the break. Modified histone y-H2AX is essential for efficient DSB recognition and processing and it is believed to have a key role in recruiting and assembling the DMA repair machinery. Consistent with these observations cells deficient in H2AX phosphorylation show genomic instability, tumor susceptibility and radiation hypersensitivity. The goal of this project is to develop a quantitative model that helps identify the role of histone y -H2AX in the process of recruitment of DMA repair proteins to DSBs. We will accomplish this aim by first developing a computational model of diffusion of chromatin associated proteins in the cell nucleus previous to DSB induction. This will help us estimate diffusion parameters and protein concentrations under normal conditions. Second we will estimate how diffusion properties and protein concentrations deviate from the previously estimated values after the induction of DSBs. These results will allow us to characterize different recruitment models and quantitatively identify the role of y -H2AX in protein recruitment after DSB induction. This project will be developed in close collaboration with experimental biologists. Relevance to Public Health: Quantification of repair/mis-repair reactions is essential to further understand processes of chromosome aberration formation such as those observed in carcinogenesis and cancer progression and after exposure to DMA-damaging agents. Since we are interested in processes that respond to radiation, our studies will help to better predict radiation sensitivity and cancer risks from environmental or occupational exposures, to estimate past exposures to radiation, and to improve tumor radiotherapy treatments.