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Tim Formosa

Professor of Biochemistry

B.S. University of California, Davis

Ph.D. University of California, San Francisco

Research

References

tim@biochem.utah.edu

Tim Formosa's PubMed Literature Search

Research

We use yeast to study a highly conserved complex called FACT, which binds to nucleosomes and reorganizes them into an alternative structure whose nature remains poorly understood. This ability to reorganize the basic subunits of chromatin is essential for the viability of eukaryotic cells. When FACT subunits are mutated in yeast, both RNA transcription and DNA replication are affected, so FACT is both a transcription factor and a DNA replication factor. We use purified proteins to examine the activity of FACT in vitro, and we use mutations in FACT subunits to study its functions in vivo. This combination of genetics and biochemistry allows us to study the important features of yFACT more rapidly and more fully than would be possible using either approach alone. In collaboration with Chris Hill's lab, we have also studied the 3-dimensional structure of FACT using X-ray crystallography. The projects in this lab therefore provide solid training in several important areas of science.

Chromatin proteins such as histones and other DNA binding factors typically limit the accessibility of DNA in eukaryotic cells. Remodeling factors solve this problem by using ATP hydrolysis to move nucleosomes along the DNA, making different sequences accessible in the linkers between nucleosomes. FACT makes nucleosomal DNA accessible, but it does not use ATP hydrolysis and it does not move the nucleosomes. We are interested in determining how FACT accomplishes this.

One set of approaches we use involves studying how purified components behave in vitro. This biochemistry allows us to ask defined mechanistic questions about the activity of FACT. Another set of approaches involves asking questions about what FACT does in living cells. This genetic analysis allows us to ask which processes actually use yFACT and how its activities in the purified systems relate to its functions in vivo. We have also collaborated with David Stillman's lab to study the role of FACT in promoting the formation of transcription intermediates in whole cells. Biochemistry tells us how proteins and DNA behave in isolation, but it cannot tell us what is important about their functions in cells. Genetics tells us what is important about cellular processes, but provides little specific information about mechanisms. Using biochemistry and genetics together is therefore synergistic and allows insights to be gained into the fundamental workings of cells. We are using this balanced approach to explore the function of yFACT in mediating transcription and replication.

Other projects in the lab use the same approaches to study other transcription factors, such as Spt6 and Spn1, and the role of the proteasome in regulating cellular function.

 

References