Our research focus is the mechanism and regulation of RNA synthesis by the enzyme RNA polymerase II. In eukaryotes, RNA polymerases are components of large protein machines that integrate many regulatory signals to precisely control gene expression. Most subunits of the transcription machinery are essential for viability, and regulation of transcription is a key step controlling cell identity, growth, development and stress response. Since the core transcription machinery is the target of many signaling pathways, identifying regulated and rate-limiting steps in transcription initiation leads to understanding how many biological signals converge to control specific programs of gene regulation. Misregulation of transcription is a major cause of human disease. Research in the laboratory aims to decipher fundamental and conserved mechanisms used by the transcription machinery and its regulatory factors.
The two major research areas in our laboratory are: (i) the mechanism of transcription initiation, and (ii) mechanisms used by factors that activate transcription. We use a multi disciplinary approach including biochemical, molecular, genetic, structural, and biophysical methods to uncover new mechanisms used in gene regulation. Much of our work uses new technologies and approaches to understand the action of large protein complexes, which are often regulated by surprisingly flexible and dynamic protein-protein interactions. These new approaches are also adaptable for understanding the architecture, conformational changes and mechanisms of large protein and protein-DNA complexes involved in other cellular processes.
We use S. cerevisiae (budding yeast) as our experimental system because of the powerful mix of biochemistry and genetics approaches available. Since the transcription machinery and its regulatory factors are well conserved throughout evolution, gene regulatory mechanisms in yeast are nearly always used in mammalian cells. These mechanisms form the molecular basis for understanding regulated and rate-limiting steps that are at the endpoint of pathways controlling cell growth, development and stress response.
Structure of the TATA binding protein (TBP; red) in complex with DNA. This protein-DNA complex nucleates assembly of the polymerase II transcription machinery at a promoter.
(see Kim et al, 1993; Geiger et al, 1996)
|last updated June 2012|