The enzymes of the SUMOylation pathway play a pivotal role in a number of cellular processes including nuclear transport, signal transduction, stress responses and cell cycle progression. Covalent modification of proteins by small ubiquitin-related modifiers (SUMOs) may modulate their stability and subcellular compartmentalisation. Three classes of enzymes are involved in the process of SUMOylation; an activating enzyme (E1), conjugating enzyme (E2) and protein ligases (E3s). UBE2I is a member of the E2 conjugating enzyme family and cloning of the human gene was first described by Wang et al. (1996). The human UBE2I cDNA contains 7 exons sharing 56% and 100% identity with the yeast and mouse homologues (Nacerddine et al., 2005; Shi et al., 2000; Wang et al., 1996). The candidate tumor suppressor gene Fragile Histidine Triad (FHIT) located on 3p14.2 is deleted in many types of human cancer. UBE2I binds to FHIT and this interaction is thought to be involved in the degradation of S and M phase cyclins and cell cycle control. Proliferating Cell Nuclear Antigen (PCNA) a DNA polymerase sliding clamp involved in DNA synthesis and repair is a substrate for UBE2I. SUMOylation of PCNA is mediated by UBE2I and occurs on a specific lysine residue - K146 - which may also be modified by ubiquitin (Hoege et al., 2002). Crystallography has revealed that UBE2I forms part of a 4 protein complex consisting of a NUP358/RANBP2 E3 ligase domain, and SUMO1 conjugated to the carboxy-terminal domain of RANGAP1. A model for the complex has been proposed in which NUP358/RANBP2 acts as an E3 by binding both SUMO and UBE2I to position the SUMO-E2-thioester in an optimal orientation to enhance conjugation (Reverter and Lima, 2005). SUMOylation of Amyloid Precursor Protein (APP) was reported to be associated with decreased levels of beta amyloid (Abeta) aggregates, suggesting a role in the pathogenesis of Alzheimer’s Disease (AD). An investigation into single nucleotide polymorphisms (SNPs) in the UBE2I gene have shown an association between this and the risk of late onset AD (Ahn et al., 2009).
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