Transcriptional regulation involves an interplay between regulatory proteins and the general transcriptional machinery and is a key mechanism for control of many biological processes. Coordination of gene expression is critical for healthy development, differentiation, immune responses, and the maintenance of cellular homeostasis. Disruptions in the program of transcriptional regulation are observed in many diseased states such as cancer. Therefore, it is important to develop an understanding of fundamental transcriptional mechanisms. The long-term objective of this study is to understand how eukaryotic basal transcription factors function in transcription and gene regulation. The model system that the principal investigator uses is the transcription of human small nuclear (sn) RNA genes. The snRNA gene family represents a large collection of genes that have important functions in the cell. These genes have similar promoter architectures and yet RNA polymerase II transcribes some of these genes while RNA polymerase III transcribes others. Thus, these genes offer a powerful system to analyze the molecular mechanisms of transcription for both RNA polymerase II and III. Transcription of human snRNA genes, regardless of polymerase specificity, requires the basal transcription factor referred to as snRNA activating protein complex (SNAPc). This multi-protein complex binds specifically to the core-promoter regions of human snRNA genes. SNAPc is composed of at least five proteins SNAP 19, SNAP43, SNAP45, SNAP5O, and SNAP 190. In addition, the TATA-box binding protein (TBP) co-purifies with SNAPc. Each of these proteins is required for snRNA transcription by both RNA polymerases II and III. These proteins also contribute to the regulated transcription of human snRNA genes. Human U6 gene transcription by RNA polymerase III is repressed by the retinoblastoma tumor suppressor protein (Rb) and this may involve communication between Rb and SNAPc. The principal investigator has chosen to study SNAPc because this complex plays a key role in human snRNA gene transcription by both RNA polymerases II and III and is a direct target of regulatory proteins such as Rb. This project will employ molecular techniques to understand the function of individual members of SNAPc for regulated transcription by RNA polymerases II and III.
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