The ubiquitin-proteasome system handles the majority of controlled proteolysis in eukaryotes. Defects in the ubiquitin-proteasome system have been implicated in diseases ranging from cancers to neurodegenerative disorders. However, the precise role of ubiquitin-proteasome-mediated degradation in health and disease is far from clear. A major challenge is to link specific substrates directly to a particular degradation pathway. Here, we review genome-wide approaches that have been developed in recent years to comprehensively identify ubiquitylated substrates of a particular pathway. Components of the ubiquitin-proteasome system are attractive drug targets, as illustrated by the efficacy of some proteasome inhibitors in the treatment of multiple myeloma. Information that has emerged from these studies could reveal novel drug targets and strategies for treating human diseases.
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