EXCEED THE SPACE PROVIDED. The long range goal of this research is to contribute to an understanding of the biochemical mechanisms underlying the regulation of eukaryotic messenger RNA synthesis. Throughout the course of this grant, we have sought to determine, at the molecular level, how the activity of mammalian RNA polymerase II is controlled by the action of the general initiation factors and a set of elongation factors that function together to direct accurate initiation and efficient elongation. This work led to the purification and characterization of the RNA polymerase II general initiation factors and elongation factors Elongin and ELL. Our studies of RNA polymerase II elongation factor Elongin opened up a new and productive line of research on the mechanism of action of the von HippeI-Lindau (VHL) tumor suppressor protein. This work led to the discovery that the VHL protein is an integral component of a new family of Elongin BC-based E3 ubiquitin ligases. During the extension of this MERIT Award, we plan to extend our studies of the mechanism and regulation of RNA polymerase II transcription and of the mechanism of action the VHL tumor suppressor protein as outlined below. The overall aims remain the same as in the last competing renewal: (1) Purification and analysis of transcription factors that control the activity of mammalian RNA polymerase II during elongation. (2) Analysis of the biochemical mechanism of promoter-specific transcription by RNA polymerase II. (3) Investigation of the mechanisms of action of the VHL ubiquitin ligase complex and of members of the family of related Elongin BC-based ubiquitin ligases. PERFORMANCE SITE ========================================Section End===========================================
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