Protein degradation via the ubiquitin-proteasome system is essential for cells to grow and divide. Consistent with this role, numerous ubiquitin ligases (E3s) that promote protein degradation, as well as deubiquitinating enzymes (DUBs) that antagonize E3 function, are mutated in cancer cells. However, the targets of most of these enzymes remain unknown. The Benanti Lab is using yeast as a model system to determine how conserved E3s and DUBs recognize and select their substrates, and to develop proteome-wide approaches to identify targets of these critical enzymes.