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: 7229133
• 负责人: Francisco Javier Arsuaga
• 金额: $ 7.5万
• 依托单位: SAN FRANCISCO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229133
• 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; Condition; 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; H2AFX gene; 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; Rate; Reaction; Recruitment Activity; Research; Research Personnel; Role; Simulate; Sister Chromatid; Testing; Work; base; biodosimetry; cancer genetics; cancer risk; carcinogenesis; cell injury; cohesin; cohesion; 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）是细胞最危险的DMA损伤形式。当DSB 如果没有被忠实地修复，它们会引入染色体畸变（即基因组的大重排）。 染色体畸变是外源性和内源性DNA损伤剂（例如， 来自代谢反应、不完全重组事件、辐射、某些化学物质的自由基） 并且经常与癌发生和癌症进展的过程相关。之一 真核细胞对DSB诱导的最早反应是组蛋白H2 AX的磷酸化 分子（由y-H2 AX表示）在断裂附近。修饰的组蛋白γ-H2 AX对于 有效的DSB识别和处理，它被认为在招募和 组装DMA修复机器与这些观察结果一致，缺乏H2 AX的细胞 磷酸化显示基因组不稳定性、肿瘤易感性和辐射超敏性。的目标 本项目旨在建立一个定量模型，帮助确定组蛋白γ-H2 AX在细胞凋亡中的作用。 DNA修复蛋白向DSB的募集过程。我们将通过首先开发一个 DSB前细胞核中染色质相关蛋白扩散的计算模型 诱导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 在诱导DSB后的先前估计值。这些结果将使我们能够描述 不同的募集模型，并定量确定γ-H2 AX在蛋白质募集后的作用， 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/误修复反应的量化对于进一步 了解染色体畸变形成的过程，如在致癌过程中观察到的过程 和癌症进展以及暴露于DMA损伤剂后。既然我们对 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，并 改善肿瘤放射治疗。