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

DNA 双链断裂修复的计算机建模（试点）

基本信息

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
项目类别：
财政年份：
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

项目摘要

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（DSBs）是细胞DMA损伤中最危险的形式。当dsb