Tumor progression involves changes in transcriptional regulation that result in altered states of gene expression. Central to the process of transcriptional regulation is the activation of transcription by RNA polymerases I, II, and III. This transcriptional activation involves the interplay of site-specific activators bound to sites near or far from the transcriptional start site with basal factors bound to core-promoter elements located near the transcriptional start site. This project represents the fusion of two current projects-Enhancer Function and Viral Transactivation-and its overall goal is to understand how site-specific activators and core-promoter-binding basal factors communicate amongst themselves and with each other to regulate transcription. We use herpes simplex virus (HSV) to probe these mechanisms. When HSV infects a cell, the infecting virion deposits a transcriptional activator called VP16 into the infected cell. VP16 initiates a cascade of viral gene transcription by directing formation of a multiprotein-DNA complex, called the VP16-induced complex, with two cellular coregulators-Oct-1, a POU-domain transcriptional activator, and HCF-1, a chromatin-associated regulator of cell proliferation-on HSV immediate-early promoters. In uninfected cells, Oct-1 plays important roles in activation of RNA polymerase II and III transcription by different core-promoter-binding basal factors in different promoter contexts and HCF-1 plays one or more important roles in promoting cell proliferation through association with chromatin. We study these cellular and viral proteins together and separately to understand the mechanisms of transcriptional regulation in human cells. We will determine the structure and function of the herpes-simplex-virus VP16-induced complex and its constituent members, HCF-1, Oct-1, and VP16; elucidate the roles of basal core-promoter-binding factors in both RNA polymerase II and III transcription; and identify mechanisms of transcriptional activation domain function.
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