David A. Brow

Credentials: RNA biology and gene expression in eukaryotes

Position title: Professor

Phone: (608) 262-1475

Address:
4204B Biochemical Sciences Building
440 Henry Mall, Madison, WI 53706

The Brow Lab Website

Education

• BA 1979, University of California, Santa Cruz (Harry Noller)
• PhD 1986, University of California, San Diego (E. Peter Geiduschek)
• Postdoctoral, 1986-89, University of California, San Francisco (Christine Guthrie)

Honors & Awards

• Searle Scholar Award, 1990
• Shaw Scientist Award, 1991
• UW-Madison Vilas Associate Award, 1999-2001
• UW SMPH Dean’s Teaching Award, 2001-2002
• UW Chancellor’s Distinguished Teaching Award, 2016
• Fellow, American Academy of Microbiology, 2016
• Fellow, American Association for the Advancement of Science, 2016

Research Interests

We study two essential biological “nanomachines” of gene expression, the spliceosome and RNA polymerase II (Pol II), using brewer’s yeast as a model system. Our studies on the spliceosome focus on U6 RNA and the dynamic RNA-RNA and RNA-protein interactions required for its assembly into the active site. Using genetic suppression analysis and in vitro biochemistry, we have defined a complex network of interactions that involves 3 RNAs (U2, U4, and U6), two helicases (Prp28 and Brr2), an RNA-binding protein (Prp24), and the largest and most conserved spliceosomal protein (Prp8). In collaboration with Sam Butcher’s lab, we recently solved the crystal structure of the core U6 snRNP (Prp24 bound to U6 RNA) at 1.7 Å resolution (see Figure 1).

figure-1

Figure 1. From EJ Montemayor et al. (2014) Nature Struct. Molec. Biol. 21: 544-551.

Our work on Pol II focuses on transcription termination as a strategy for gene regulation. We discovered and are characterizing a pathway that uses the helicase Sen1 and a collection of RNA-binding proteins, including Nrd1 and Nab3, to terminate synthesis of short transcripts by Pol II (see Figure 2). This pathway aids in the synthesis of non-coding RNAs, as well as the regulation of mRNA levels. Mutations in the human homolog of Sen1 result in neuro-degenerative disorders. We are exploring the function and targets of the Sen1 termination pathway by genetics, genomics, biochemistry, and structural biology.
brow-2

Figure 2. From DA Brow (2011) Molec. Cell 42: 717-718.

Publications

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Lipinski, K.A., J. Chi, X. Chen, A.A. Hoskins, and D.A. Brow. (2022). Yeast U6 snRNA made by RNA polymerase II is less stable but functional. RNA (New York, N.Y.), 28: 1606-1620.
Mabin, J.W., P.W. Lewis, D.A. Brow, and H. Dvinge. (2021). Human spliceosomal snRNA sequence variants generate variant spliceosomes. RNA (New York, N.Y.), 27: 1186-1203.
Montemayor, E.J., J.M. Virta, S.M. Hayes, Y. Nomura, D.A. Brow, and S.E. Butcher. (2020). Molecular basis for the distinct cellular functions of the Lsm1-7 and Lsm2-8 complexes. RNA (New York, N.Y.), 26: 1400-1413.
Kuehner, J.N., and D.A. Brow. (2019). Regulation of a Eukaryotic Gene by GTP-Dependent Start Site Selection and Transcription Attenuation. Molecular cell, 74: 634.
Brow, D.A. (2019). An Allosteric Network for Spliceosome Activation Revealed by High-Throughput Suppressor Analysis in Saccharomyces cerevisiae. Genetics, 212: 111-124.
Montemayor, E.J., A.L. Didychuk, A.D. Yake, G.K. Sidhu, D.A. Brow, and S.E. Butcher. (2018). Architecture of the U6 snRNP reveals specific recognition of 3'-end processed U6 snRNA. Nature communications, 9: 1749.
Didychuk, A.L., S.E. Butcher, and D.A. Brow. (2018). The life of U6 small nuclear RNA, from cradle to grave. RNA (New York, N.Y.), 24: 437-460.
Didychuk, A.L., E.J. Montemayor, T.J. Carrocci, A.T. DeLaitsch, S.E. Lucarelli, W.M. Westler, D.A. Brow, A.A. Hoskins, and S.E. Butcher. (2017). Usb1 controls U6 snRNP assembly through evolutionarily divergent cyclic phosphodiesterase activities. Nature communications, 8: 497.
Chen, X., K. Poorey, M.N. Carver, U. Müller, S. Bekiranov, D.T. Auble, and D.A. Brow. (2017). Transcriptomes of six mutants in the Sen1 pathway reveal combinatorial control of transcription termination across the Saccharomyces cerevisiae genome. PLoS genetics, 13: e1006863.
Montemayor, E.J., A.L. Didychuk, H. Liao, P. Hu, D.A. Brow, and S.E. Butcher. (2017). Structure and conformational plasticity of the U6 small nuclear ribonucleoprotein core. Acta crystallographica. Section D, Structural biology, 73: 1-8.