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

DNA 双链断裂修复的计算机建模（试点）

• 批准号: 7751325
• 负责人: Francisco Javier Arsuaga
• 金额: $ 7.44万
• 依托单位: SAN FRANCISCO STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7751325
• 关键词: Algorithms; Binding; Binding Proteins; Biological Assay; Cell Nucleus; Cells; Chemicals; Chromatin; Chromatin Modeling; Chromosomal Instability; Chromosome abnormality; Chromosomes; Collaborations; Computer Simulation; Computer software; Computing Methodologies; DNA Double Strand Break; DNA Sequence Rearrangement; DNA repair protein; Data; Data Set; Diffuse; Diffusion; Double Strand Break Repair; Eukaryotic Cell; Event; Exposure to; Fluorescence; Fluorescence Recovery After Photobleaching; Free Radicals; Genetic Recombination; Genome; Genomic Instability; Goals; Hereditary Disease; Histones; Hypersensitivity; Individual; Label; Malignant Neoplasms; Measures; Metabolic; Modeling; Occupational Exposure; Phosphorylation; Photobleaching; Physics; Play; Polymers; Positioning Attribute; Predisposition; Process; Property; Proteins; Protocols documentation; Public Health; Publishing; Radiation; Radiation Tolerance; Radiation therapy; Radiobiology; Reaction; Recruitment Activity; Research; Research Personnel; Role; San Francisco; Simulate; Sister Chromatid; Testing; Universities; Work; base; biodosimetry; cancer genetics; cancer risk; carcinogenesis; cell injury; cohesin; cohesion; flexibility; human H2AX protein; improved; interest; repaired; research study; response; software development; tumor; tumor progression

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.

双链断裂（DSB）是电池损伤的最危险形式。当DSB为时 他们没有忠实维修，他们引入了染色体畸变（即基因组的大重排）。 染色体畸变是外源和内源性DMA损害剂的特征（例如， 自由基来自代谢反应，不完整的重组事件，辐射，某些化学物质） 并且经常与癌变和癌症进展过程有关。中的一个 真核细胞对DSB诱导的最早反应是组蛋白H2AX的磷酸化 分子（用y -h2ax表示）在破裂的附近。修改的组蛋白Y-H2AX对于 有效的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，缺乏H2AX 磷酸化显示基因组不稳定性，肿瘤敏感性和辐射超敏反应。目标 该项目是开发一个定量模型，该模型有助于识别组蛋白y -H2AX在 将DMA修复蛋白募集到DSB的过程。我们将首先开发一个 DSB之前的染色质蛋白扩散的计算模型 就职。这将有助于我们在正常下估计扩散参数和蛋白质浓度 状况。其次，我们将估计扩散特性和蛋白质浓度如何偏离 DSB诱导后先前估计的值。这些结果将使我们能够表征 不同的招聘模型，并定量确定Y -H2AX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。 与公共卫生有关：维修/错误修复反应的量化对于进一步的反应至关重要 了解染色体像差形成的过程，例如在癌变中观察到的过程 和癌症的进展以及暴露于DMA损害剂后。由于我们对 响应辐射的过程，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，估计过去对辐射的暴露以及 改善肿瘤放射治疗。