Many cell cycle transitions are controlled by ubiquitin-mediated proteolysis of key cell cycle regulators (1 ). The ubiquitin system targets substrates to the proteasome by attaching a polyubiquitin chain (2 ). The traditional ubiquitin transfer reaction involves a minimum of three enzymes: E1, which mediates the ATP-dependent activation of ubiquitin, and the E2 ubiquitin-conjugating enzyme (UBC), which, together with an E3 ubiquitin ligase, transfers ubiquitin to the target protein. Despite the successful identification of many ubiquitin ligases, only a few of their substrates are known. This is because ubiquitin ligases share conserved motifs, whereas substrates seem to have little in common other than critical lysine residues.
