New Insights into the Role of E2s in the Pathogenesis of Diseases: Lessons Learned from UBE2O

  • Hormaechea-Agulla, Daniel (Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center) ;
  • Kim, Youngjo (Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University) ;
  • Song, Min Sup (Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center) ;
  • Song, Su Jung (Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University)
  • Received : 2018.01.06
  • Accepted : 2018.03.13
  • Published : 2018.03.31


Intracellular communication via ubiquitin (Ub) signaling impacts all aspects of cell biology and regulates pathways critical to human development and viability; therefore aberrations or defects in Ub signaling can contribute to the pathogenesis of human diseases. Ubiquitination consists of the addition of Ub to a substrate protein via coordinated action of E1-activating, E2-conjugating and E3-ligating enzymes. Approximately 40 E2s have been identified in humans, and most are thought to be involved in Ub transfer; although little information is available regarding the majority of them, emerging evidence has highlighted their importance to human health and disease. In this review, we focus on recent insights into the pathogenetic roles of E2s (particularly the ubiquitin-conjugating enzyme E2O [UBE2O]) in debilitating diseases and cancer, and discuss the tantalizing prospect that E2s may someday serve as potential therapeutic targets for human diseases.


Supported by : Cancer Prevention Research Institute of Texas, Department of Defense, National Institutes of Health, NRF, KHIDI


  1. Andersen, P.L., Zhou, H., Pastushok, L., Moraes, T., McKenna, S., Ziola, B., Ellison, M.J., Dixit, V.M., and Xiao, W. (2005). Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A. J. Cell Biol.170, 745-755.
  2. Banerjee, S., Brooks, W.S., and Crawford, D.F. (2007). Inactivation of the ubiquitin conjugating enzyme UBE2Q2 causes a prophase arrest and enhanced apoptosis in response to microtubule inhibiting agents. Oncogene26, 6509-6517.
  3. Barrera, M.J., Aguilera, S., Castro, I., Cortes, J., Bahamondes, V., Quest, A.F.G., Molina, C., Gonzalez, S., Hermoso, M., Urzua, U., et al. (2016). Pro-inflammatory cytokines enhance ERAD and ATF6alpha pathway activity in salivary glands of Sjogren's syndrome patients. J. Autoimmun.75, 68-81.
  4. Bartke, T., Pohl, C., Pyrowolakis, G., and Jentsch, S. (2004). Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase. Mol. Cell14, 801-811.
  5. Berleth, E.S., and Pickart, C.M. (1996). Mechanism of ubiquitin conjugating enzyme E2-230K: catalysis involving a thiol relay? Biochemistry 35, 1664-1671.
  6. Budny, B., Badura-Stronka, M., Materna-Kiryluk, A., Tzschach, A., Raynaud, M., Latos-Bielenska, A., and Ropers, H.H. (2010). Novel missense mutations in the ubiquitination-related gene UBE2A cause a recognizable X-linked mental retardation syndrome. Clin. Genet.77, 541-551.
  7. Buetow, L., and Huang, D.T. (2016). Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat. Rev. Mol. Cell Biol.17, 626-642.
  8. Burr, M.L., van den Boomen, D.J., Bye, H., Antrobus, R., Wiertz, E.J., and Lehner, P.J. (2013). MHC class I molecules are preferentially ubiquitinated on endoplasmic reticulum luminal residues during HRD1 ubiquitin E3 ligase-mediated dislocation. Proc. Natl. Acad. Sci. USA110, 14290-14295.
  9. Ceccarelli, D.F., Tang, X., Pelletier, B., Orlicky, S., Xie, W., Plantevin, V., Neculai, D., Chou, Y.C., Ogunjimi, A., Al-Hakim, A., et al. (2011). An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. Cell 145, 1075-1087.
  10. Ceccaldi, R., Sarangi, P., and D'Andrea, A.D. (2016). The Fanconi anaemia pathway: new players and new functions. Nat. Rev. Mol. Cell Biol.17, 337-349.
  11. Chen, H., Wu, G., Gao, S., Guo, R., Zhao, Z., Yuan, H., Liu, S., Wu, J., Lu, X., Yuan, X., et al. (2017a). Discovery of Potent Small-molecule inhibitors of ubiquitin-conjugating enzyme UbcH5c from alpha-Santonin derivatives. J. Med. Chem.60, 6828-6852.
  12. Chen, M., Nowak, D.G., Narula, N., Robinson, B., Watrud, K., Ambrico, A., Herzka, T.M., Zeeman, M.E., Minderer, M., Zheng, W., et al. (2017b). The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein. J. Cell Biol.216, 641-656.
  13. Cheng, J., Fan, Y.H., Xu, X., Zhang, H., Dou, J., Tang, Y., Zhong, X., Rojas, Y., Yu, Y., Zhao, Y., et al. (2014). A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways. Cell Death Dis. 5, e1079.
  14. de Pril, R., Fischer, D.F., Roos, R.A., and van Leeuwen, F.W. (2007). Ubiquitin-conjugating enzyme E2-25K increases aggregate formation and cell death in polyglutamine diseases. Mol. Cell Neurosci. 34, 10-19.
  15. Debonneville, C., and Staub, O. (2004). Participation of the ubiquitinconjugating enzyme UBE2E3 in Nedd4-2-dependent regulation of the epithelial $Na^+$ channel. Mol. Cell. Biol.24, 2397-2409.
  16. Dikic, I., Wakatsuki, S., and Walters, K.J. (2009). Ubiquitin-binding domains - from structures to functions. Nat. Rev. Mol. Cell Biol.10, 659-671.
  17. Espinosa, A., Hennig, J., Ambrosi, A., Anandapadmanaban, M., Abelius, M.S., Sheng, Y., Nyberg, F., Arrowsmith, C.H., Sunnerhagen, M., and Wahren-Herlenius, M. (2011). Anti-Ro52 autoantibodies from patients with Sjogren's syndrome inhibit the Ro52 E3 ligase activity by blocking the E3/E2 interface. J. Biol. Chem. 286, 36478-36491.
  18. Falvey, C.M., O'Donovan, T.R., El-Mashed, S., Nyhan, M.J., O'Reilly, S., and McKenna, S.L. (2017). UBE2L6/UBCH8 and ISG15 attenuate autophagy in esophageal cancer cells. Oncotarget 8, 23479-23491.
  19. Fiesel, F.C., Moussaud-Lamodiere, E.L., Ando, M., and Springer, W. (2014). A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently. J. Cell Sci.127, 3488-3504.
  20. Garnett, M.J., Mansfeld, J., Godwin, C., Matsusaka, T., Wu, J., Russell, P., Pines, J., and Venkitaraman, A.R. (2009). UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. Nat. Cell Biol.11, 1363-1369.
  21. Ge, C., Che, L., Ren, J., Pandita, R.K., Lu, J., Li, K., Pandita, T.K., and Du, C. (2015). BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1. Proc. Natl. Acad. Sci. USA 112, E1210-E1219.
  22. Gehrke, S.G., Riedel, H.D., Herrmann, T., Hadaschik, B., Bents, K., Veltkamp, C., and Stremmel, W. (2003). UbcH5A, a member of human E2 ubiquitin-conjugating enzymes, is closely related to SFT, a stimulator of iron transport, and is up-regulated in hereditary hemochromatosis. Blood 101, 3288-3293.
  23. Geisler, S., Vollmer, S., Golombek, S., and Kahle, P.J. (2014). The ubiquitin-conjugating enzymes UBE2N, UBE2L3 and UBE2D2/3 are essential for Parkin-dependent mitophagy. J. Cell Sci. 127, 3280-3293.
  24. Grabbe, C., Husnjak, K., and Dikic, I. (2011). The spatial and temporal organization of ubiquitin networks. Nat. Rev. Mol. Cell Biol. 12, 295-307.
  25. Guo, Y., An, L., Ng, H.M., Sy, S.M., and Huen, M.S. (2017). An E2-guided E3 Screen Identifies the RNF17-UBE2U Pair as Regulator of the Radiosensitivity, Immunodeficiency, Dysmorphic Features, and Learning Difficulties (RIDDLE). Syndrome Protein RNF168. J. Biol. Chem. 292, 967-978.
  26. Haddad, D.M., Vilain, S., Vos, M., Esposito, G., Matta, S., Kalscheuer, V.M., Craessaerts, K., Leyssen, M., Nascimento, R.M., Vianna-Morgante, A.M., et al. (2013). Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair parkindependent mitophagy. Mol. Cell 50, 831-843.
  27. Han, J.W., Zheng, H.F., Cui, Y., Sun, L.D., Ye, D.Q., Hu, Z., Xu, J.H., Cai, Z.M., Huang, W., Zhao, G.P., et al. (2009). Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234-1237.
  28. Hao, Y.H., Doyle, J.M., Ramanathan, S., Gomez, T.S., Jia, D., Xu, M., Chen, Z.J., Billadeau, D.D., Rosen, M.K., and Potts, P.R. (2013). Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination. Cell 152, 1051-1064.
  29. Harper, J.W., and King, R.W. (2011). Stuck in the middle: drugging the ubiquitin system at the e2 step. Cell 145, 1007-1009.
  30. Hershko, A., Ciechanover, A., Heller, H., Haas, A.L., and Rose, I.A. (1980). Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis. Proc. Natl. Acad. Sci. USA 77, 1783-1786.
  31. Hira, A., Yoshida, K., Sato, K., Okuno, Y., Shiraishi, Y., Chiba, K., Tanaka, H., Miyano, S., Shimamoto, A., Tahara, H., et al. (2015). Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. Am. J. Hum. Genet. 96, 1001-1017.
  32. Hoeller, D., Crosetto, N., Blagoev, B., Raiborg, C., Tikkanen, R., Wagner, S., Kowanetz, K., Breitling, R., Mann, M., Stenmark, H., et al. (2006). Regulation of ubiquitin-binding proteins by monoubiquitination. Nat. Cell Biol.8, 163-169.
  33. Ikeda, F., Deribe, Y.L., Skanland, S.S., Stieglitz, B., Grabbe, C., Franz-Wachtel, M., van Wijk, S.J., Goswami, P., Nagy, V., Terzic, J., et al. (2011). SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis. Nature 471, 637-641.
  34. Jin, S.M., and Youle, R.J. (2012). PINK1- and Parkin-mediated mitophagy at a glance. J. Cell Sci. 125, 795-799.
  35. Kaiser, P., Seufert, W., Hofferer, L., Kofler, B., Sachsenmaier, C., Herzog, H., Jentsch, S., Schweiger, M., and Schneider, R. (1994). A human ubiquitin-conjugating enzyme homologous to yeast UBC8. J. Biol. Chem. 269, 8797-8802.
  36. Kamadurai, H.B., Souphron, J., Scott, D.C., Duda, D.M., Miller, D.J., Stringer, D., Piper, R.C., and Schulman, B.A. (2009). Insights into ubiquitin transfer cascades from a structure of a UbcH5B approximately ubiquitin-HECT(NEDD4L). complex. Mol. Cell 36, 1095-1102.
  37. Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., and Shimizu, N. (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605-608.
  38. Klemperer, N.S., Berleth, E.S., and Pickart, C.M. (1989). A novel, arsenite-sensitive E2 of the ubiquitin pathway: purification and properties. Biochemistry 28, 6035-6041.
  39. Koenig, P.A., Nicholls, P.K., Schmidt, F.I., Hagiwara, M., Maruyama, T., Frydman, G.H., Watson, N., Page, D.C., and Ploegh, H.L. (2014). The E2 ubiquitin-conjugating enzyme UBE2J1 is required for spermiogenesis in mice. J. Biol. Chem.289, 34490-34502.
  40. Koken, M.H., Smit, E.M., Jaspers-Dekker, I., Oostra, B.A., Hagemeijer, A., Bootsma, D., and Hoeijmakers, J.H. (1992). Localization of two human homologs, HHR6A and HHR6B, of the yeast DNA repair gene RAD6 to chromosomes Xq24-q25 and 5q23-q31. Genomics 12, 447-453.
  41. Komander, D., and Rape, M. (2012). The ubiquitin code. Annu. Rev. Biochem. 81, 203-229.
  42. Komander, D., Clague, M.J., and Urbe, S. (2009). Breaking the chains: structure and function of the deubiquitinases. Nat. Rev. Mol. Cell Biol. 10, 550-563.
  43. Kottgen, A., Pattaro, C., Boger, C.A., Fuchsberger, C., Olden, M., Glazer, N.L., Parsa, A., Gao, X., Yang, Q., Smith, A.V., et al. (2010). New loci associated with kidney function and chronic kidney disease. Nat. Genet. 42, 376-384.
  44. Lam, S.Y., Murphy, C., Foley, L.A., Ross, S.A., Wang, T.C., and Fleming, J.V. (2014). The human ubiquitin conjugating enzyme UBE2J2 (Ubc6). is a substrate for proteasomal degradation. Biochem. Biophys. Res. Commun. 451, 361-366.
  45. Lechtenberg, B.C., Rajput, A., Sanishvili, R., Dobaczewska, M.K., Ware, C.F., Mace, P.D., and Riedl, S.J. (2016). Structure of a HOIP/E2-ubiquitin complex reveals RBR E3 ligase mechanism and regulation. Nature 529, 546-550.
  46. Liang, K., Volk, A.G., Haug, J.S., Marshall, S.A., Woodfin, A.R., Bartom, E.T., Gilmore, J.M., Florens, L., Washburn, M.P., Sullivan, K.D., et al. (2017). Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia. Cell 168, 59-72.
  47. Liu, W., Shang, Y., Zeng, Y., Liu, C., Li, Y., Zhai, L., Wang, P., Lou, J., Xu, P., Ye, Y., et al. (2014). Dimeric Ube2g2 simultaneously engages donor and acceptor ubiquitins to form Lys48-linked ubiquitin chains. EMBO J. 33, 46-61.
  48. Lobitz, S., and Velleuer, E. (2006). Guido Fanconi (1892-1979).: a jack of all trades. Nat. Rev. Cancer 6, 893-898.
  49. Lu, D., Huang, J., Ma, X., Gu, N., Zhang, J., Zhang, H., and Guo, X. (2017). Rs46522 in the Ubiquitin-Conjugating Enzyme E2Z Gene Is Associated with the Risk of Coronary Artery Disease in Individuals of Chinese Han Population with Type 2 Diabetes. J. Diabetes Res. 2017, 4501794.
  50. Luo, H., Qin, Y., Reu, F., Ye, S., Dai, Y., Huang, J., Wang, F., Zhang, D., Pan, L., Zhu, H., et al. (2016). Microarray-based analysis and clinical validation identify ubiquitin-conjugating enzyme E2E1 (UBE2E1). as a prognostic factor in acute myeloid leukemia. J. Hematol. Oncol. 9, 125.
  51. Machida, Y.J., Machida, Y., Chen, Y., Gurtan, A.M., Kupfer, G.M., D'Andrea, A.D., and Dutta, A. (2006). UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol. Cell 23, 589-596.
  52. Mashtalir, N., Daou, S., Barbour, H., Sen, N.N., Gagnon, J., Hammond-Martel, I., Dar, H.H., Therrien, M., and Affar el, B. (2014). Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O. Mol. Cell 54, 392-406.
  53. Menezes, J., Acquadro, F., Wiseman, M., Gomez-Lopez, G., Salgado, R.N., Talavera-Casanas, J.G., Buno, I., Cervera, J.V., Montes-Moreno, S., Hernandez-Rivas, J.M., et al. (2014). Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia 28, 823-829.
  54. Morreale, F.E., Testa, A., Chaugule, V.K., Bortoluzzi, A., Ciulli, A., and Walden, H. (2017). Mind the Metal: A Fragment Library-Derived Zinc Impurity Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural Rearrangements. J. Med. Chem. 60, 8183-8191.
  55. Mou, L., Zhang, Q., Diao, R., Cai, Z., and Gui, Y. (2015). A functional variant in the UBE2B gene promoter is associated with idiopathic azoospermia. Reprod. Biol. Endocrinol. 13, 79.
  56. Nguyen, A.T., Prado, M.A., Schmidt, P.J., Sendamarai, A.K., Wilson-Grady, J.T., Min, M., Campagna, D.R., Tian, G., Shi, Y., Dederer, V., et al. (2017). UBE2O remodels the proteome during terminal erythroid differentiation. Science 357, doi: 10.1126/science.aan0218
  57. Pickart, C.M. (2001). Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503-533.
  58. Plafker, K.S., and Plafker, S.M. (2015). The ubiquitin-conjugating enzyme UBE2E3 and its import receptor importin-11 regulate the localization and activity of the antioxidant transcription factor NRF2. Mol. Biol. Cell 26, 327-338.
  59. Plechanovova, A., Jaffray, E.G., Tatham, M.H., Naismith, J.H., and Hay, R.T. (2012). Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489, 115-120.
  60. Polge, C., Attaix, D., and Taillandier, D. (2015a). Role of E2-Ubconjugating enzymes during skeletal muscle atrophy. Front. Physiol. 6, 59.
  61. Popovic, D., Vucic, D., and Dikic, I. (2014). Ubiquitination in disease pathogenesis and treatment.Nat. Med.20, 1242-1253.
  62. Pruneda, J.N., Smith, F.D., Daurie, A., Swaney, D.L., Villen, J., Scott, J.D., Stadnyk, A.W., Le Trong, I., Stenkamp, R.E., Klevit, R.E., et al. (2014). E2-Ub conjugates regulate the kinase activity of Shigella effector OspG during pathogenesis. EMBO J. 33, 437-449.
  63. Psyrri, A., Kalogeras, K.T., Kronenwett, R., Wirtz, R.M., Batistatou, A., Bournakis, E., Timotheadou, E., Gogas, H., Aravantinos, G., Christodoulou, C., et al. (2012). Prognostic significance of UBE2C mRNA expression in high-risk early breast cancer. A Hellenic Cooperative Oncology Group (HeCOG). Study. Ann. Oncol. 23, 1422-1427.
  64. Pulvino, M., Liang, Y., Oleksyn, D., DeRan, M., Van Pelt, E., Shapiro, J., Sanz, I., Chen, L., and Zhao, J. (2012). Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A. Blood 120, 1668-1677.
  65. Ramanathan, H.N., Zhang, G., and Ye, Y. (2013). Monoubiquitination of EEA1 regulates endosome fusion and trafficking. Cell Biosci. 3, 24.
  66. Ramatenki, V., Dumpati, R., Vadija, R., Vellanki, S., Potlapally, S.R., Rondla, R., and Vuruputuri, U. (2017a). Identification of New Lead Molecules Against UBE2NL Enzyme for Cancer Therapy. Appl. Biochem. Biotechnol. 182, 1497-1517.
  67. Ramatenki, V., Dumpati, R., Vadija, R., Vellanki, S., Potlapally, S.R., Rondla, R., and Vuruputuri, U. (2017b). Targeting the ubiquitinconjugating enzyme E2D4 for cancer drug discovery-a structurebased approach. J. Chem. Biol. 10, 51-67.
  68. Roest, H.P., van Klaveren, J., de Wit, J., van Gurp, C.G., Koken, M.H., Vermey, M., van Roijen, J.H., Hoogerbrugge, J.W., Vreeburg, J.T., Baarends, W.M., et al. (1996). Inactivation of the HR6B ubiquitinconjugating DNA repair enzyme in mice causes male sterility associated with chromatin modification. Cell 86, 799-810.
  69. Schelpe, J., Monte, D., Dewitte, F., Sixma, T.K., and Rucktooa, P. (2016). Structure of UBE2Z enzyme provides functional insight into specificity in the FAT10 protein conjugation machinery. J. Biol. Chem. 291, 630-639.
  70. Schmidt, C.K., Galanty, Y., Sczaniecka-Clift, M., Coates, J., Jhujh, S., Demir, M., Cornwell, M., Beli, P., and Jackson, S.P. (2015). Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair. Nat. Cell Biol. 17, 1458-1470.
  71. Schumacher, F.R., Siew, K., Zhang, J., Johnson, C., Wood, N., Cleary, S.E., Al Maskari, R.S., Ferryman, J.T., Hardege, I., Yasmin, et al. (2015). Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia. EMBO Mol. Med. 7, 1285-1306.
  72. Scott, D.C., Hammill, J.T., Min, J., Rhee, D.Y., Connelly, M., Sviderskiy, V.O., Bhasin, D., Chen, Y., Ong, S.S., Chai, S.C., et al. (2017). Blocking an N-terminal acetylation-dependent protein interaction inhibits an E3 ligase.Nat. Chem. Biol. 13, 850-857.
  73. Semplici, F., Meggio, F., Pinna, L.A., and Oliviero, S. (2002). CK2-dependent phosphorylation of the E2 ubiquitin conjugating enzyme UBC3B induces its interaction with beta-TrCP and enhances betacatenin degradation. Oncogene 21, 3978-3987.
  74. Shembade, N., Ma, A., and Harhaj, E.W. (2010). Inhibition of NFkappaB signaling by A20 through disruption of ubiquitin enzyme complexes. Science327, 1135-1139.
  75. Shukla, S., Allam, U.S., Ahsan, A., Chen, G., Krishnamurthy, P.M., Marsh, K., Rumschlag, M., Shankar, S., Whitehead, C., Schipper, M., et al. (2014). KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated beta-TrCP1 degradation. Neoplasia 16, 115-128.
  76. Somasagara, R.R., Spencer, S.M., Tripathi, K., Clark, D.W., Mani, C., Madeira da Silva, L., Scalici, J., Kothayer, H., Westwell, A.D., Rocconi, R.P., et al. (2017). RAD6 promotes DNA repair and stem cell signaling in ovarian cancer and is a promising therapeutic target to prevent and treat acquired chemoresistance. Oncogene 36, 6680-6690.
  77. Stahl, E.A., Raychaudhuri, S., Remmers, E.F., Xie, G., Eyre, S., Thomson, B.P., Li, Y., Kurreeman, F.A., Zhernakova, A., Hinks, A., et al. (2010). Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508-514.
  78. Stewart, M.D., Ritterhoff, T., Klevit, R.E., and Brzovic, P.S. (2016). E2 enzymes: more than just middle men. Cell Res. 26, 423-440.
  79. Sun, L., and Fang, J. (2016). E3-Independent constitutive monoubiquitination complements histone methyltransferase activity of SETDB1.Mol. Cell 62, 958-966.
  80. Townsley, F.M., Aristarkhov, A., Beck, S., Hershko, A., and Ruderman, J.V. (1997). Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase. Proc. Natl. Acad. Sci. USA 94, 2362-2367.
  81. van Ree, J.H., Jeganathan, K.B., Malureanu, L., and van Deursen, J.M. (2010). Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation. J. Cell Biol. 188, 83-100.
  82. Vander Heiden, M.G., Cantley, L.C., and Thompson, C.B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033.
  83. Vila, I.K., Yao, Y., Kim, G., Xia, W., Kim, H., Kim, S.J., Park, M.K., Hwang, J.P., Gonzalez-Billalabeitia, E., Hung, M.C., et al. (2017). A UBE2O-AMPKalpha2 axis that promotes tumor initiation and progression offers opportunities for therapy. Cancer Cell 31, 208-224.
  84. Vittal, V., Shi, L., Wenzel, D.M., Scaglione, K.M., Duncan, E.D., Basrur, V., Elenitoba-Johnson, K.S., Baker, D., Paulson, H.L., Brzovic, P.S., et al. (2015). Intrinsic disorder drives N-terminal ubiquitination by Ube2w. Nat. Chem. Biol. 11, 83-89.
  85. Vourc'h, P., Martin, I., Bonnet-Brilhault, F., Marouillat, S., Barthelemy, C., Pierre Muh, J., and Andres, C. (2003). Mutation screening and association study of the UBE2H gene on chromosome 7q32 in autistic disorder. Psychiatr. Genet. 13, 221-225.
  86. Watanabe, T.K., Kawai, A., Fujiwara, T., Maekawa, H., Hirai, Y., Nakamura, Y., and Takahashi, E. (1996). Molecular cloning of UBE2G, encoding a human skeletal muscle-specific ubiquitin-conjugating enzyme homologous to UBC7 of C. elegans. Cytogenet. Cell Genet. 74, 146-148.
  87. Wefes, I., Mastrandrea, L.D., Haldeman, M., Koury, S.T., Tamburlin, J., Pickart, C.M., and Finley, D. (1995). Induction of ubiquitinconjugating enzymes during terminal erythroid differentiation. Proc. Natl. Acad. Sci. USA 92, 4982-4986.
  88. Wenzel, D.M., Stoll, K.E., and Klevit, R.E. (2011). E2s: structurally economical and functionally replete. Biochem. J. 433, 31-42.
  89. Xin, H., Lin, W., Sumanasekera, W., Zhang, Y., Wu, X., and Wang, Z. (2000). The human RAD18 gene product interacts with HHR6A and HHR6B. Nucleic Acids Res.28, 2847-2854.
  90. Xu, K., Jiang, L., Zhang, M., Zheng, X., Gu, Y., Wang, Z., Cai, Y., Dai, H., Shi, Y., Zheng, S., et al. (2016). Type 2 diabetes risk allele UBE2E2 is associated with decreased glucose-stimulated insulin release in elderly Chinese han individuals. Medicine (Baltimore) 95, e3604.
  91. Yamauchi, T., Hara, K., Maeda, S., Yasuda, K., Takahashi, A., Horikoshi, M., Nakamura, M., Fujita, H., Grarup, N., Cauchi, S., et al. (2010). A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat. Genet. 42, 864-868.
  92. Yanagitani, K., Juszkiewicz, S., and Hegde, R.S. (2017). UBE2O is a quality control factor for orphans of multiprotein complexes. Science 357, 472-475.
  93. Ye, Y., and Rape, M. (2009). Building ubiquitin chains: E2 enzymes at work. Nat. Rev. Mol. Cell Biol. 10, 755-764.
  94. Yokota, T., Nagai, H., Harada, H., Mine, N., Terada, Y., Fujiwara, H., Yabe, A., Miyazaki, K., and Emi, M. (2001). Identification, tissue expression, and chromosomal position of a novel gene encoding human ubiquitin-conjugating enzyme E2-230k. Gene 267, 95-100.
  95. Yu, B., Swatkoski, S., Holly, A., Lee, L.C., Giroux, V., Lee, C.S., Hsu, D., Smith, J.L., Yuen, G., Yue, J., et al. (2015). Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9. Proc. Natl. Acad. Sci. USA 112, E1724-E1733.
  96. Yu, H., Xiang, P., Pan, Q., Huang, Y., Xie, N., and Zhu, W. (2016). Ubiquitin-conjugating enzyme E2T is an independent prognostic factor and promotes gastric cancer progression. Tumour Biol. 37, 11723-11732.
  97. Zhang, Y., Zhou, X., Zhao, L., Li, C., Zhu, H., Xu, L., Shan, L., Liao, X., Guo, Z., and Huang, P. (2011). UBE2W interacts with FANCL and regulates the monoubiquitination of Fanconi anemia protein FANCD2. Mol. Cells 31, 113-122.
  98. Zhang, X., Zhang, J., Bauer, A., Zhang, L., Selinger, D.W., Lu, C.X., and Ten Dijke, P. (2013a). Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated monoubiquitination of SMAD6. EMBO J. 32, 996-1007.
  99. Zhang, X., Zhang, J., Zhang, L., van Dam, H., and ten Dijke, P. (2013b). UBE2O negatively regulates TRAF6-mediated NF-kappaB activation by inhibiting TRAF6 polyubiquitination. Cell Res. 23, 366-377.
  100. Zhang, B., Deng, C., Wang, L., Zhou, F., Zhang, S., Kang, W., Zhan, P., Chen, J., Shen, S., Guo, H., et al. (2017). Upregulation of UBE2Q1 via gene copy number gain in hepatocellular carcinoma promotes cancer progression through beta-catenin-EGFR-PI3K-Akt-mTOR signaling pathway. Mol. Carcinog. 57, 201-215.
  101. Zhou, W., Xu, J., Li, H., Xu, M., Chen, Z.J., Wei, W., Pan, Z., and Sun, Y. (2017). Neddylation E2 UBE2F promotes the survival of lung cancer cells by activating CRL5 to degrade NOXA via the K11 linkage. Clin. Cancer Res. 23, 1104-1116.