The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including regulated and targeted proteosomal degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). UBE2S is a member of the E2 conjugating enzyme family and cloning of the human gene was first described by Liu et al. (1992). UBE2S shares 38% identity with yeast Ubc4 and is highly similar to ubiquitin carrier proteins in the core region containing the active-site cysteine. The tumour suppressor protein Von Hippel-Lindau (VHL) forms part of an E3 ligase complex that targets the transcription factor Hypoxia-Inducible Factor-1A (HIF-1A) for degradation. VHL associates with and is targeted by UBE2S for ubiquitin-mediated proteolysis in human cell lines. Over expression of UBE2S increases tumor cell proliferation, invasion, and metastasis through the VHL-HIF pathway and has been found to correlate positively with HIF-1A in tumour cell lines (Jung et al., 2006). An RNAi screen identified UBE2S as an anaphase-promoting complex (APC/C) auxiliary factor that promotes mitotic exit from the spindle-assembly checkpoint (SAC). Knockdown of UBE2S prolongs drug-induced mitotic arrest and suppresses mitotic slippage. UBE2S can also elongate ubiquitin chains initiated by the E2 enzymes UBE2C and UBE2D1, enhancing the degradation of APC/C substrates by the proteasome (Garnett et al., 2009). Recently UBE2S has been shown to assemble K11-specific chains for human and Drosophila APC/C. Chain specific activity of UBE2S is dependent on cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1. Depletion of UBE2S has been shown to result in severe spindle defects and mitotic delay (Williamson et al., 2009).
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