Evolution of ubiquitin-specific proteases

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Ubiquitin is a small protein that is attached to other cellular proteins. In many cases further ubiquitin molecules are added to the first to form chains of various topologies - these chains can affect the stability or function of the proteins to which they are attached. A mammalian cell contains hundreds of different enzymes that direct the attachment of ubiquitin and assembly of chains, and in the order of one hundred cell that can edit or remove the chains ("deubiquitinating enzymes", or DUBs). In simpler organisms such as yeast there are far fewer DUBs, and it may be that during evolution DUB genes have been duplicated and have taken on new functions. Despite their involvement in critical regulatory pathways the evolution of DUBs has not been well studied.***My laboratory was responsible for the discovery of one of the first mammalian DUBs to be identified. This enzyme (designated USP4) has one very close relative (USP15), and one that is slightly more distant (USP11). We hypothesize that these genes arose from gene duplication events, and propose to use computational analysis of large protein and DNA databases to determine how the three genes evolved (when the duplications occurred and in what order). We have mice that have mutations in their USP4 or USP15 genes, and by crossing these strains together we will determine whether mice require at least one functional gene and reveal the consequences of deficiency in these proteins. We will also explore the function of these genes in the zebrafish, a species that has an altered version of USP15.  USP4 and USP15 represent the ideal model system to explore the evolution of deubiquitinating enzymes. These studies will contribute to our long term objective, which is to understand of how cellular networks can be "rewired" following gene duplications. **