Small ubiquitin-like Modifiers (SUMOs) are a family of small, related proteins that can be enzymatically attached to a target protein by a post-translational modification process termed SUMOylation. There are four known SUMOs (SUMO1-4). All SUMO proteins share a conserved ubiquitin domain and a C-terminal diglycine cleavage/attachment site. Following cleavage of a C-terminal prosegment, the C-terminal glycine residue of SUMO is enzymatically attached to a lysine residue on a target protein. In humans, SUMO is conjugated to a variety of molecules in the presence of the SAE1/UBA2 SUMO-activating (E1) enzyme and the UBE2I/Ubc9 SUMO-conjugating (E2) enzyme. In yeast, the SUMO-activating (E1) enzyme is Aos1/Uba2p. SUMOylation can occur without the requirement of a specific SUMO ligase (E3), where SUMO is transferred directly from UBE2I/Ubc9 to specific substrates. Unlike SUMO1, which is usually conjugated to proteins as a monomer, SUMO2 and SUMO3 are known to form high molecular weight polymers on proteins. SUMO precursor processing and deconjugation are catalyzed by a family of cysteine proteases known as SUMO-specific proteases (SENPs) and DeSUMOylating Isopeptidase 1.