Specificity and Disease in the Ubiquitin system

Post-translational modification of a target protein by the covalent attachment of ubiquitin is an essential regulatory process.  Ubiquitination drives the cell cycle, DNA damage repair, wound healing, protein trafficking, endocytosis and homeostasis. Perhaps unsurprisingly, defects in the ubiquitin system are commonly associated with a variety of disease states including cancer and neurodegeneration. My long-term goal is to understand on a mechanistic level how ubiquitin is physically and chemically ligated to a substrate. Intrinsic to this is the question of specificity, how a given target, a specific lysine, and the specific pathway are selected on the molecular level.  The Fanconi Anemia DNA repair pathway is an example of the importance of ubiquitination, with a single monoubiquitination event being the crucial step of the entire pathway. It is an exquisitely specific system, employing just one E2 to target a single lysine on each of two homologous substrates. This signal is absolutely required for the repair of DNA interstrand crosslinks. At the opposite end of the spectrum, the E3 ligase Parkin, mutated in early onset hereditary Parkinsonism, has multiple substrates, targets multiple lysines, and collaborates with many E2 conjugating enzymes. Thus each system presents an intriguing set of questions regarding substrate specificity, chain type, and regulation.  I will present an overview of the work my lab has done to address the questions of specificity and disease in the ubiquitin system.


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Dr Simon Cook
The Brian Heap Seminar Room