J. Wade Harper
Department of Pathology
Harvard Medical School
New Research Building, Room 940
77 Ave. Louis Pasteur
Boston, MA 02115
Tel: 617-432-6590
Fax: 617-432-6591
Email: wade_harper@hms.harvard.edu
Web Page: The Harper Lab Page
The cell cycle is composed of a series of transitions that culminate in the duplication of chromosomes through the process of DNA replication and the separation of chromosomes into daughter cells through the process of mitosis. Cell cycle transitions are frequently controls through ubiquitin mediated proteolysis of proteins that negatively regulate cell cycle progression. This laboratory studies the proteins and regulatory circuits that catalyze cell cycle and checkpoint dependent protein turnover using a variety of genetic, proteomic, and cell biological approaches.
A major interest is a family of E3 ubiquitin ligases which use cullin proteins as a scaffold to assemble an E3 catalytic center and substrate specific adaptor proteins. This lab identified F-box proteins as substrate adaptors for Cul1, BTB proteins as adaptors for Cul3 and DCAF proteins as adaptors for Cul4. During the last decade, we have identified a number of cell cycle and other signaling pathways that rely on cullin-based adaptors.
A major goal has been to identify new genes involved in cell cycle and checkpoint control. To this end, we have collaborated with the Elledge Lab at Harvard Medical School to develop shRNA libraries targeting the UPP and other classes of signaling molecules. These libraries are being used to identify UPP genes involved in cell cycle checkpoint control. These studies are providing new insight into how the ubiquitin system contributes to activation of critical cellular processes.
A second major goal of our work is to develop proteomic and informatic approaches that allow for the rapid identification of protein interactions within signaling networks and within particular classes of proteins - for example specific classes of ubiquitin pathway genes, work that we are performing in collaboration with Steve Gygi at Harvard Medical School. These tools are also useful in the systematic interrogation of genes that emerge from RNAi screens. The centerpiece of this platform is a suite of software called CompPASS which greatly simplifies parallell processing of large proteomic datasets and facilitates the identification of interaction networks. We have recently applied this approach to a family of enzymes called deubiquitinating enzymes, which remove ubiquitin from proteins. This effort has led to the identification of candidate pathways and targets for a large fraction of the Dubs expressed in the human genome. These methods are being applied to other gene families and to genes involved in cell cycle and checkpoint control.
References:
- Sowa, M.E., Bennett, E.J., Gygi, S.P., and Harper, J.W. Defining the Human Deubiquitinating Enzyme Interaction Landscape. Cell, 2009. in press.
- Schlabach et al., Cancer proliferation gene discovery through functional genomics. Science. 2008 319:620-4.
- Westbrook et al., SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature. 2008 452:370-4.
- Jin, J., Li, X., Gygi, S.P., and Harper, J.W. Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Nature. 2007 447:1135-8.
BBS webpage updated 12/02/2009