J. Wade Harper
Department of Cell Biology
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
Ubiquitin and ubiquitin-like (UBL) protein conjugation systems control a vast array of cellular processes, and impact virtually every biological system. In this process, UBLs are activated through an activation and conjugation cascade before attachment to targt proteins. Conjugation of ubiquitin itself is best known for its role in protein turnover via the proteasome, but ubiquitin conjugation can also provide regulatory functions in solid-state signaling networks.
Our work seeks to employ systematic genetic and proteomic approaches to elucidate the mechanisms and biology of ubiquitin and UBL protein conjugation systems. Much of our efforts have been devoted to elucidating the components and targets of a superfamily of E3 ubiquitin ligases referred to as cullin-RING ubiquitin ligases. These E3s employ a cullin scaffold and various families of substrate receptor proteins to assemble dozens of E3s targeting hundreds of proteins. We have explored the roles of these E3s in cell cycle and DNA damage checkpoint control and are currently employing systematic proteomic approaches to identify substrates and biological processes more many poorly understood CRLs. We have recently elucidated the network organization of the human autophagy system, a distinct UBL conjugation system that controls turnover of cytoplasmic proteins and organelles in the lysosome.
A major emphasis of our work is to discover genes and mechanism that contribute DNA damage checkpoint control, a process that intimately employs the ubiquitin system to control particular events. We employ genome-wide RNAi screening approaches as well as proteomic analysis of pathway components to identify signaling networks controlling DNA repair, including the recent identification of a novel SLX4-containing Holliday junction resolvase complex important for DNA double-strand break repair.
Finally, a major emphasis is placed on the development of software tools and approaches for performing protein network analysis via interaction proteomics. We have developed the CompPASS proteomics platform, which facilitates proteomic studies in multiple systems. Current efforts in the lab seek to take advantage of quantitative proteomic approaches to understand dynamic changes in signaling networks after stimulation.
References:
- Sowa, M., Bennett, EJ, Gygi, SP, and Harper JW (2009) Defining the deubiquitinating enzyme interactome landscape. Cell 138:389-403.
- Svendsen JM, Smogorzewska A, Sowa ME, O’Connell BC, Gygi SP, Elledge SJ, Harper JW. (2009) Mammalian SLX4 assembles a Holliday Junction resolvase and is required for DNA repair. Cell 138:63-77.
- Jin, J., Li, X., Gygi, S.P., and Harper, J.W. (2007) Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Nature 447:1135-1138.
- Schulman BA, Harper JW. (2009) Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol. 10:319-331.
BBS webpage updated 5/10/2010