Analysis of RNA polymerase fidelity and its implications for cellular function

该项目提出检查RNA聚合酶的保真度，以及这种保真度是如何通过 环境因素，影响疾病和衰老的进展。冷静！错误被认为 是细胞功能病理改变的基础例如，泛素-B和（Jamyloid）的错误转录本 前体蛋白在神经元中被检测到，它们的产物在神经元的蛋白质沉积物中积累。 老年痴呆症和唐氏综合症患者。这些产物的积累与疾病进展有关， 并被假定与该疾病的病因有关。这项建议将探讨 RNA聚合酶的合成，以及暴露于不同试剂的环境对其的改变。一 全面的保真度测定将用于在宽范围内确定聚合错误率， 序列背景，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，目的是识别易错的RNA聚合酶。 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 详细表征RNA聚合酶的保真度，并研究如何之间的关系， 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。 老化的过程。 基因转录是蛋白质合成的第一步。这项研究探讨了基因的准确性， 转录，这种准确性是如何由环境调制，以及如何改变这种准确性可以是 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进展和衰老影响的关键。

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.