The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including regulated and targeted proteasomal 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). UBE2R1 is a member of the E2 conjugating enzyme family and cloning of the human gene was first described by Plon et al. (1993). UBE2R1 plays an essential role in promoting the G1-S-phase transition of the eukaryotic cell cycle; it is phosphorylated on serine residues (S203, S222 and S231) present in the acidic tail domain a, region critical for its cell cycle function. Casein Kinase type II (CK2) mediated phosphorylation of UBE2R1 increases ubiquitylation of Sic-1 in the presence of the E3 ligase S-phase kinase-associated protein 1/Cullin/F-box/Cdc4 (SCFCdc4) during cell cycle progression (Sadowski et al., 2007). Specific binding of CK2 phosphorylated UBE2R1 to beta-TRCP (β-TRCP) - the substrate recognition unit of the SCF ligase - enhances degradation of its substrate beta-catenin (Semplici et al., 2002). UBE2R1 also catalyzes polyubiquitylation of a substrate recruited by the Skp1-Cullin 1-F-box protein-ROC1 E3 ubiquitin ligase. Downregulation of UBE2R1 following let-7 over expression in primary fibroblasts, results in reduced SCF activity, stabilization of the Wee1 kinase, and an increased fraction of the cells in G(2)/M (Legesse-Miller et al., 2009).
Legesse-Miller A, Elemento O, Pfau SJ, Forman JJ, Tavazoie S, Coller HA (2009) let-7 Overexpression leads to an increased fraction of cells in G2/M, direct down-regulation of Cdc34, and stabilization of Wee1 kinase in primary fibroblasts. J Biol Chem 284, 6605-9.
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