interaction, in particular to DUBs substrate recognition. This is predicted because of the hydrophobic cleft present in the DUSP domain of USP15 and that some protein interactions with DUSP containing USPs do not occur without these domains. The DUSP domain displays a novel tripod-like fold comprising three helices and an anti-parallel beta-sheet made of three strands. This fold resembles the legs (helices) and seat (beta-sheet) of the tripod. Within most DUSP domains in USPs there is a conserved sequence of amino acids known as the PGPI motif. This is a sequence of four amino acids; proline, glycine, proline and isoleucine, which packs against the three-helix bundle and is highly ordered. Role in disease The full extent of the role of DUBs in diseases remains to be elucidated. Their involvement in disease is predicted due to known roles in physiological processes that are involved in disease states; including cancer and neurological disorders. The enzyme USP28 is over-expressed in different types of cancer such as colon or lung. In addition, USP28 deubiquitinates and stabilizes important oncogenes such as c-Myc, Notch1, c-jun or ΔNp63. In squamous tumors, USP28 regulates the resistance to chemotherapy regulating DNA repair via ΔNp63-Fanconia anemia pathway axis. The deubiquitinating enzymes UCH-L3 and YUH1 are able to hydrolyse mutant ubiquitin UBB+1 despite of the fact that the glycine at position 76 is mutated. UCH-L1 levels are high in various types of malignancies (cancer). Role in the Cell Cycle DUBs play an active role in modulating the cell cycle. Ubiquitin-specific-processing protease (USP) is a family of deubiquitinating enzymes that play a crucial role in cell cycle regulation. Two such enzymes include USP17 and USP44. USP17 regulates pathways responsible for progressing cells through the cell cycle. Its targets include regulators of Ras, CDK2, and Cyclin A. USP44 plays an important role in anaphase initiation. New research into the mitotic checkpoint has revealed a novel role for USP44 in regulating cell cycle progression. USP Regulation of Ras The ERK Pathway allows for the transduction of external mitogenic signals into intracellular signals promoting cellular proliferation. One of the key regulators of this pathways is Ras, a GTPase that, upon activation, binds GTP to “turn on” the subsequent signaling cascade. Ras converting enzyme 1 (RCE1) post-translationally cleaves the 3 residues on the C-terminus of Ras, allowing Ras to properly localize to the plasma membrane. USP17 acts to deubiquitinate K63-ubiquitin domains on RCE1. Such stabilization of