Research Program: Genetic Mechanisms of Cancer
Assistant Professor, Department of Genetics, Cell Biology, and Development

koepp015@umn.edu
612-624-4201 — office
612-624-4807 — lab
Preferred method of contact: e-mail

Dr. Koepp received a Ph.D. in microbiology and molecular genetics in 1998 at Harvard University Medical School. She conducted postdoctoral training (1998-2002) in the laboratory of Stephen J. Elledge at the Baylor College of Medicine. She joined the faculty the Department of Genetics, Cell Biology and Development at the University of Minnesota in 2002.

Research Interests

Cell growth and division is coordinately regulated to follow a scripted program of events. Perturbation of the cell cycle can lead to genomic instability or tumorigenesis. Cell cycle progression is controlled by factors whose expression oscillates throughout the cell cycle. One key mechanism for regulating the expression of cell cycle factors is ubiquitin-dependent proteolysis.

The Koepp laboratory investigates the role of a family of modularubiquitin ligases, enzymes that regulate the ubiquitination of target proteins, in cell cycle regulation. These ubiquitin ligases, called SCF complexes, are composed of at least four subunits: Skp1, Cdc53/Cullin, Rbx1/Roc1 and anF-box-containing protein. Skp1, Cdc53/Cullin and Rbx1/Roc1 are core components of each SCF complex, while the F-box protein determines substrate specificity. A large family of F box proteins has been identified, suggesting thatSCF complexes regulate the ubiquitination of numeroussubstrates. SCF complexes are conserved among eukaryotes; thus both human cells and the yeast Saccharomyces cerevisiae are used as systems to study SCF function. The power of yeast genetics is used in S. cerevisiae while human cells are used for cell biology and biochemistry studies.

Downregulation of protein function via proteolysis-dependent mechanisms is important for many cellular functions. SCF complexes are likely to be used in many pathways, given their combinatorial nature and the extraordinary numbers of F-box proteins in higher eukaryotes. The development of a generalized mechanism for SCF complexes will have tremendous utility to many fields of molecular research.

Thus, it is important to understand how the SCF functions and how it is regulated, particularly in mammalian cells. Furthermore, determining how and why proteins are targeted for destruction could have enormous implications in drug design. The lab has discovered an SCF complex that ubiquitinates the cell cycle factor cyclin E and is studying the mechanism and regulation of the association of cyclin E with this complex not only as a model for SCF function but also to understand the implications for cell cycle control.

There are many F-box proteins for which no substrate has been identified. Also, putative substrates of SCF complexes have been identified but the identity of their cognate F-box protein is unknown. Even in the case of known SCF substrates, such as cyclin E, additional SCF complexes may play a role in their regulation. To address these issues, the lab is developing systematic assays to identify substrate/F-box protein interactions.

Selected Publications

Swaminathan S, Kile AC, MacDonald EM, Koepp DM. Yra1 is required for S phase entry and affects Dia2 binding to replication origins. Mol Cell Biol. 2007; 27:4674-4684.

Kang Y, Zhang N, Koepp DM, Walters KJ. Ubiquitin receptor proteins hHR23a and hPLIC2 interact. J Mol Biol. 2007; 365:1093-1101.

Liu F, Zhang N, Zhou X, Hanna PE, Wagner CR, Koepp DM, Walters KJ. Arylamine N-acetyltransferase aggregation and constitutive ubiquitylation. J Mol Biol, 2006;361:482-492.

Zhang W, Koepp DM. Fbw7 isoform interaction contributes to cyclin E proteolysis. Mol Cancer Res. 2006;4:935-943.

Koepp, D.M., Kile, A.C., Swaminathan, S., Rodriguez-Rivera, V. (2006) The F-box protein Dia2 regulates DNA replication. Mol Biol Cell. 2006;17:1540-1548.

Koepp, D.M., Schaefer, L.K., Ye, X., Keyomarsi, K., Chu, C., Harper, J.W., Elledge, S.J. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science, 2001;294:173-177.

Skowyra D., Koepp D.M., Kamura T., Conrad M.N., Conaway R.C., Conaway J.W., Elledge S.J., Harper J.W. (1999) Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1. Science 284:662-5.

Kamura T., Koepp D.M., Conrad M.N., Skowyra D., Moreland R.J., Iliopoulos O., Lane W.S., Kaelin W.G. Jr,Elledge S.J., Conaway R.C., Harper J.W., Conaway J.W. (1999) Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 284:657-61

Winston J.T., Koepp D.M., Zhu C., Elledge S.J., Harper J.W. (1999) A family of mammalian F-box proteins. Curr. Biol. 9:1180-2.