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Analysis of RNA polymerase fidelity and its implications for cellular function

RNA 聚合酶保真度分析及其对细胞功能的影响

基本信息

批准号：
7847663
负责人：
MIGUEL GARCIA-DIAZ
金额：
$ 24.34万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-16 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847663
关键词：
Address Affect Aging Aging-Related Process Alleles Alzheimer&apos s Disease Amyloid beta-Protein Precursor Biological Biological Assay Bypass Cell physiology Cells Coupled DNA Damage DNA lesion DNA-Directed RNA Polymerase Deposition Development Disease Disease Progression Down Syndrome Environment Environmental Exposure Enzymes Etiology Event Exposure to Frequencies Genes Genetic Transcription Goals Hot Spot Human Lesion Link Measurement Measures Mitochondria Mitochondrial RNA Molecular Molecular Genetics Mutagenesis Mutation Neurodegenerative Disorders Neurons Pathology Patients Predisposition Process Protein Biosynthesis Protein Precursors Proteins RNA RNA Phages RNA Precursors RNA chemical synthesis Research Risk Structure System Testing Transcript Yeasts base disorder risk environmental agent human UBB protein in vivo mutant normal aging polymerization toxic metal

项目摘要

This project proposes to examine RNA polymerase fidelity, and how this fidelity is modulated by environmental agents and influences the progression of disease and aging. Transcriptions! errors are thought to underlie pathological alterations in cellular function. For instance, faulty transcripts of ubiquitin-B and (Jamyloid precursor protein are detected in neurons and their products accumulate in protein deposits of Alzheimer's and Down's syndrome patients. Accumulation of these products is linked to disease progression, and has been postulated to be implicated in the etiology of the disease. This proposal will probe the accuracy of synthesis by RNA polymerases, and its alteration by environmental exposure to different agents. A comprehensive fidelity assay will be used to determine polymerization error rates over a broad range of sequence contexts and examine the existence of mutational hot spots that might put certain genes at risk. Structure-function studies will address the basis of RNA polymerase errors with the aim of identifying errorprone alleles to analyze the in vivo consequences of low transcription fidelity. This project will provide a detailed characterization of RNA polymerase fidelity and examine how the relationship between environmental exposures and transcription fidelity can modulate susceptibility to certain diseases or the nonpathological process of aging. -Gene transcription is the first step in the synthesis of proteins. This research explores the accuracy of gene transcription, how this accuracy is modulated by the environment and how alterations of this accuracy can be detrimental to the cell. Understanding the connection between the accuracy of gene transcription and environmental exposures is key to assess its influence in the progression of disease and aging.

该项目旨在检查 RNA 聚合酶的保真度，以及这种保真度是如何通过以下因素调节的：环境因素并影响疾病和衰老的进展。转录！错误被认为是细胞功能病理改变的基础。例如，泛素-B 和 (Jamyloid 在神经元中检测到前体蛋白，其产物在神经元的蛋白质沉积物中积累阿尔茨海默氏症和唐氏综合症患者。这些产物的积累与疾病进展有关，并被认为与该疾病的病因学有关。该提案将探讨准确性 RNA 聚合酶的合成及其因环境暴露于不同试剂而发生的改变。一个综合保真度测定将用于确定广泛范围内的聚合错误率序列背景并检查可能使某些基因面临风险的突变热点的存在。结构功能研究将解决 RNA 聚合酶错误的基础，旨在识别容易出错的情况等位基因来分析低转录保真度的体内后果。该项目将提供一个 RNA聚合酶保真度的详细表征并检查之间的关系环境暴露和转录保真度可以调节对某些疾病或非病理性疾病的易感性衰老的过程。 -基因转录是蛋白质合成的第一步。本研究探讨基因的准确性转录，环境如何调节这种准确性以及如何改变这种准确性对细胞有害。了解基因转录的准确性与环境暴露是评估其对疾病和衰老进展影响的关键。