The long-term objective of this project is to understand the factors that have broad roles in transcriptional regulation in eukaryotes, utilizing the powerful combination of genetic and biochemical techniques available in the budding yeast Saccharomyces cerevisiae. Transcription can be regulated both during the initiation stage and during the process of transcript elongation. Elongation is characterized by the transit of a processive RNA polymerase across the chromatin template, requiring chromatin changes ahead of the polymerase, and reassembly of the chromatin in the freshly transcribed region. The core histones are differentially modified in the transcribed region, but more needs to be learned about the factors and mechanisms that regulate changes in histone modification. We have established a genetic link between a protein kinase (Burl) that was previously implicated in elongation and the Set2 histone methylase. Experiments proposed here will provide mechanistic insights into how Burl and other factors regulate histone methylation by Set2, and how methylation affects transcript elongation. The SUMO pathway is responsible for post-translational modification of proteins by covalent attachment of the ubiquitin-like SUMO protein to lysine residues of target substrates. Although the SUMO pathway modifies both site-specific DNA-binding proteins. and general transcription factors, its regulation and role in transcription are not completely understood. We established a new genetic link that suggests a role for SUMO modification of a general transcriptional regulator. We propose to study new components of the SUMO pathway identified by our selection and to identify their role during transcription. This project has long-range relevance to human health because precise changes in the patterns of transcription are fundamental for normal cell growth and division, and mis-regulation of gene expression can result in human disease, including cancer. Since the functions of many genes are conserved across species, these studies in a relatively simple organism are likely to provide valuable information into regulatory mechanisms that are also used in human cells. Mutations in the genes that encode homologous proteins are associated with human diseases.
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