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David Brow

Professor of Biomolecular Chemistry

Address:

535A Service Memorial Inst

Telephone:

262-1475

Email:

dabrow@wisc.edu

Research Fields:

Gene Expression

Yeast and Fungi

Research Interests

Nuclear steps in eukaryotic gene expression

Research Description

We investigate the molecular mechanisms of eukaryotic gene expression, with emphasis on transcription and pre-mRNA splicing. Because the fundamental mechanisms of gene expression are conserved among eukaryotes, we have chosen the genetically tractable yeast S. cerevisiae as a model system. Our transcription studies focus on how RNA polymerases (Pol) II and III identify a gene, and on the detailed mechanism of initiation and termination of transcription by Pol II. We use genetic, genomic, and biochemical approaches in these studies. For example, we have measured Pol II occupancy across the entire yeast genome at 100-200 base-pair resolution by chromatin immunoprecipitation, and we have identified mutations in Pol II that cause it to “read-through” transcription terminators. We discovered and are characterizing a Pol II termination pathway that uses the helicase Sen1 and appears to be most important for short transcripts. In our splicing studies we examine the mechanism and function of dynamic RNA-RNA and RNA-protein interactions in assembling the active site of the spliceosome. We defined a complex network of genetic interactions that involve two RNAs (U4 and U6), two helicases, an RNA-binding protein, and the largest and most conserved spliceosomal protein (Prp8). We use detailed mutational studies, in vitro splicing and RNA-binding assays, and structural biology to dissect the mechanism of spliceosome activation. Mutations in the human Prp8 and Sen1 genes cause retinal degeneration and progressive motor neuron dysfunction, respectively. We hope our studies will illuminate the mechanisms of these diseases.

Representative Publications

• McManus, C.J., Schwartz, M.L., Butcher, S.E., and D.A. Brow. 2007. A dynamic bulge in the U6 RNA inernal stem-loop functions in spliceosome assembly and activation. RNA. 13:2252-2265.
• Bae, E., Reiter, N.J., Bingman, C.A., Kwan, S.S., Lee, D., Phillips Jr., G.N., Butcher, S.E., and D.A. Brow. 2007. Structure and interactions of the first three RNA recognition motifs of splicing factor Prp24. J. Mol. Biol. 13:1447-1458.
• Steinmetz, E.J., Warren, C.L., Kuehner, J.N., Panbehi, B., Ansari, A.Z., and D.A. Brow. 2006. Genome-wide distribution of yeast RNA polymerase II and its control by Sen1 helicase. Molec. Cell. 24:735-746.
• Kuehner, J.N and D.A. Brow. 2006. Quantitative analysis of in vivo initiator selection by yeast RNA polymerase II supports a scanning model. J. Biol. Chem. 281: 14119-14128.
• Steinmetz, E.J., S.B.H. Ng, J.P. Cloute and D.A. Brow. 2006. Cis- and trans-acting determinants of transcription termination by yeast RNA polymerase II. Molec. Cell. Biol. 26: 2688-2696.