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.
