Analysis of RNA polymerase fidelity and its implications for cellular function

这个项目计划检查RNA聚合酶的保真度，以及这种保真度是如何通过 环境因素，并影响疾病和衰老的进展。抄本！错误被认为是 是细胞功能的病理改变的基础。例如，泛素-B和(Jamyloid)的错误转录 前体蛋白在神经元中被检测到，其产物积累在 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的进展有关， 并被认为与该病的病因学有关。这项建议将探讨其准确性 RNA聚合酶的合成及其在环境中暴露于不同试剂后的变化。一个 综合保真度分析将用于在广泛的范围内确定聚合错误率 测序背景，并检查是否存在可能使某些基因处于危险之中的突变热点。 结构-功能研究将解决RNA聚合酶错误的基础，目的是识别容易出错的错误 等位基因来分析低转录保真度在体内的后果。该项目将提供一个 详细表征了RNA聚合酶的保真度，并考察了它们之间的关系 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。这项研究探索了基因的准确性。 转录，这种准确性是如何被环境调节的，以及这种准确性的变化可能是如何 对细胞有害。了解基因转录的准确性与基因转录的关系 环境暴露是评估其在疾病进展和衰老过程中的影响的关键。

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.