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Ubiquitin and proteasomes

Sumo, ubiquitin's mysterious cousin

Key Points

  • Covalent modification by the ubiquitin-like modifier SUMO regulates various cellular processes, such as nuclear transport and cell-cycle progression. But, in contrast to ubiquitylation, which generally targets proteins for degradation, sumoylation seems to either modulate the subcellular location of proteins or enhance their stability.

  • SUMO is highly conserved from yeast to humans. Whereas invertebrates have only a single SUMO gene, three members of the SUMO family have been described in vertebrates.

  • Like ubiquitin, all SUMO forms are initially made as inactive precursors. The processing reaction is catalysed by a group of cysteine proteases, termed ubiquitin-like protein-processing enzymes (ULPs) or SUMO-specific proteases (SUSPs).

  • In contrast to ubiquitin, SUMO conjugation does not seem to lead to the formation of SUMO?SUMO chains on the substrate.

  • Sumoylation is a dynamic, reversible process. De-sumoylation is catalysed by the ULP/SUSP proteases. In yeast, de-sumoylation is essential for viability.

  • SUMO has much fewer cellular substrates than ubiquitin, but several of these targets turn out to be important cellular regulators.

  • Sumoylation of the mammalian RanGAP1 protein, a component of the nuclear import machinery, is required for binding to Ran-binding protein 2 (RanBP2) at the nuclear pore complex. This indicates either that sumoylation targets RanGAP1 to the nuclear pore complex or that it stabilizes binding to RanBP2.

  • In higher eukaryotes, most other sumoylated proteins appear to be nuclear. Intriguingly, many are found in specific subnuclear protein complexes called promyelocytic leukaemia (PML) nuclear bodies.

  • Sumoylation of PML itself regulates the assembly/stability of these nuclear bodies. Upon sumoylation of PML nuclear-body-associated proteins, including the transcription factors Daxx and p53, are recruited to nuclear bodies. Intriguingly, p53 is itself a substrate for SUMO.

  • For the NF-κB inhibitor IκBα and the ubiquitin ligase Mdm2, it has been proposed that sumoylation and ubiquitylation are functionally linked. SUMO and ubiquitin seem to compete with each other for the same lysine residues within these proteins. SUMO could thus antagonize the function of ubiquitin and act as a stabilizer of IκBα/Mdm2.

Abstract

Covalent modification of cellular proteins by the ubiquitin-like modifier SUMO regulates various cellular processes, such as nuclear transport, signal transduction, stress response and cell-cycle progression. But, in contrast to ubiquitylation, sumoylation does not tag proteins for degradation, but seems to enhance their stability or modulate their subcellular compartmentalization.

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Figure 1: Sequence alignment of SUMO family members and ubiquitin.
Figure 2: Conjugation pathway of ubiquitin and the ubiquitin-like modifier SUMO.
Figure 3: Structure of the ULP-1?SMT3 complex.
Figure 4: Sumoylation of PML modulates Daxx-mediated transcriptional repression.
Figure 5: Reversible modification of proteins by SUMO and its consequences.

References

  1. 1

    Hochstrasser, M. Ubiquitin-dependent protein degradation. Annu. Rev. Genet. 30, 405?439 (1996).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Jentsch, S. & Pyrowolakis, G. Ubiquitin and its kin: how close are the family ties? Trends Cell Biol. 10, 335?342 (2000).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Hochstrasser, M. Evolution and function of ubiquitin-like protein-conjugation systems. Nature Cell Biol. 2, E153?E157 (2000). PubMed

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Hanania, U., Furman-Matarasso, N., Ron, M. & Avni, A. Isolation of a novel SUMO protein from tomato that suppresses EIX-induced cell death. Plant J. 19, 533? 541 (1999).

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Kamitani, T., Kito, K., Nguyen, H. P., Fukuda-Kamitani, T. & Yeh, E. T. Characterization of a second member of the sentrin family of ubiquitin-like proteins. J. Biol. Chem. 273 , 11349?11353 (1998).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Boddy, M. N., Howe, K., Etkin, L. D., Solomon, E. & Freemont, P. S. PIC1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. Oncogene 13, 971 ?982 (1996).

    CAS  PubMed  Google Scholar 

  7. 7

    Okura, T. et al. Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin. J. Immunol. 157, 4277?4281 (1996).

    CAS  PubMed  Google Scholar 

  8. 8

    Matunis, M. J., Coutavas, E. & Blobel, G. A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J. Cell Biol. 135, 1457? 1470 (1996).RanGAP1 is identified as the first substrate for SUMO and the role of sumoylation in regulating the localization of RanGAP1 is shown.

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Bayer, P. et al. Structure determination of the small ubiquitin-related modifier SUMO-1. J. Mol. Biol. 280, 275? 286 (1998).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Mahajan, R., Delphin, C., Guan, T., Gerace, L. & Melchior, F. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell 88, 97?107 (1997). This important study identifies RanGAP1 as a SUMO substrate and shows that sumoylation of RanGAP1 determines its interaction with RanBP2.

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Koegl, M. et al. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96, 635? 644 (1999).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Johnson, E. S., Schwienhorst, I., Dohmen, R. J. & Blobel, G. The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer. EMBO J. 16, 5509?5519 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13

    Gong, L., Li, B., Millas, S. & Yeh, E. T. Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex. FEBS Lett. 448, 185? 189 (1999).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Desterro, J. M., Rodriguez, M. S., Kemp, G. D. & Hay, R. T. Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. J. Biol. Chem. 274, 10618 ?10624 (1999).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Desterro, J. M., Thomson, J. & Hay, R. T. Ubch9 conjugates SUMO but not ubiquitin. FEBS Lett. 417, 297?300 (1997).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Gong, L., Kamitani, T., Fujise, K., Caskey, L. S. & Yeh, E. T. Preferential interaction of sentrin with a ubiquitin-conjugating enzyme, Ubc9. J. Biol. Chem. 272, 28198? 28201 (1997).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Johnson, E. S. & Blobel, G. Ubc9p is the conjugating enzyme for the ubiquitin-like protein Smt3p. J. Biol. Chem. 272, 26799?26802 (1997).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Schwarz, S. E., Matuschewski, K., Liakopoulos, D., Scheffner, M. & Jentsch, S. The ubiquitin-like proteins SMT3 and SUMO-1 are conjugated by the UBC9 E2 enzyme. Proc. Natl Acad. Sci. USA 95, 560?564 ( 1998).

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Liu, Q. et al. The binding interface between an E2 (UBC9) and a ubiquitin homologue (UBL1). J. Biol. Chem. 274, 16979? 16987 (1999).

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Giraud, M. F., Desterro, J. M. & Naismith, J. H. Structure of ubiquitin-conjugating enzyme 9 displays significant differences with other ubiquitin-conjugating enzymes which may reflect its specificity for sumo rather than ubiquitin. Acta Crystallogr. D. Biol. Crystallogr. 54, 891?898 (1998).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Li, S. J. & Hochstrasser, M. A new protease required for cell-cycle progression in yeast. Nature 398, 246?251 (1999).This paper describes the identification of the yeast Ulp1 protease as the first SUMO de-conjugating enzyme and shows that de-sumoylation is essential for viability in yeast.

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Li, S. J. & Hochstrasser, M. The yeast ULP2 ( SMT4) gene encodes a novel protease specific for the ubiquitin-like Smt3 protein. Mol. Cell. Biol. 20, 2367? 2377 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Schwienhorst, I., Johnson, E. S. & Dohmen, R. J. SUMO conjugation and deconjugation. Mol. Gen. Genet. 263, 771?786 (2000).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Mossessova, E. & Lima, C. D. Ulp1-SUMO crystal structure and genetic analysis reveal conserved interactions and a regulatory element essential for cell growth in yeast. Mol. Cell 5, 865?876 (2000). This important study provides insight into the mechanism of substrate recognition and catalysis by Ulp1.

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Yeh, E. T., Gong, L. & Kamitani, T. Ubiquitin-like proteins: new wines in new bottles. Gene 248, 1?14 ( 2000).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Nishida, T., Tanaka, H. & Yasuda, H. A novel mammalian Smt3-specific isopeptidase 1 (SMT3IP1) localized in the nucleolus at interphase. Eur. J. Biochem. 267, 6423?6427 (2000).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Gong, L., Millas, S., Maul, G. G. & Yeh, E. T. Differential regulation of sentrinized proteins by a novel sentrin-specific protease. J. Biol. Chem. 275, 3355?3359 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Kim, K. I. et al. A new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs. J. Biol. Chem. 275, 14102?14106 (2000).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Görlich, D. & Kutay, U. Transport between the cell nucleus and the cytoplasm. Annu. Rev. Cell. Dev. Biol. 15, 607?660 ( 1999).

    PubMed  Article  Google Scholar 

  30. 30

    Saitoh, H., Pu, R., Cavenagh, M. & Dasso, M. RanBP2 associates with Ubc9p and a modified form of RanGAP1. Proc. Natl Acad. Sci. USA 94, 3736?3741 ( 1997).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Mahajan, R., Gerace, L. & Melchior, F. Molecular characterization of the SUMO-1 modification of RanGAP1 and its role in nuclear envelope association. J. Cell Biol. 140, 259?270 ( 1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Matunis, M. J., Wu, J. & Blobel, G. SUMO-1 modification and its role in targeting the Ran GTPase-activating protein, RanGAP1, to the nuclear pore complex. J. Cell Biol. 140, 499?509 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Rout, M. P. et al. The yeast nuclear pore complex: composition, architecture, and transport mechanism. J. Cell Biol. 148, 635?651 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Takahashi, Y., Mizoi, J., Toh, E. A. & Kikuchi, Y. Yeast Ulp1, an Smt3-specific protease, associates with nucleoporins. J. Biochem. 128, 723?725 ( 2000).

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Epps, J. L. & Tanda, S. The Drosophila semushi mutation blocks nuclear import of bicoid during embryogenesis. Curr. Biol. 8, 1277?1280 ( 1998).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Kamitani, T., Nguyen, H. P. & Yeh, E. T. Preferential modification of nuclear proteins by a novel ubiquitin-like molecule. J. Biol. Chem. 272 , 14001?14004 (1997).

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Guo, A. et al. The function of PML in p53-dependent apoptosis. Nature Cell Biol. 2, 730?736 ( 2000).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Fogal, V. et al. Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J. 19, 6185? 6195 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Muller, S., Matunis, M. J. & Dejean, A. Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J. 17, 61?70 (1998). This study identifies PML as a substrate for SUMO and implicates sumoylation of PML in the regulation of its compartmentalization in nuclear bodies.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Sternsdorf, T., Jensen, K. & Will, H. Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1. J. Cell Biol. 139, 1621?1634 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Kamitani, T., Nguyen, H. P., Kito, K., Fukuda-Kamitani, T. & Yeh, E. T. Covalent modification of PML by the sentrin family of ubiquitin-like proteins. J. Biol. Chem. 273, 3117?3120 (1998).

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Kamitani, T. et al. Identification of three major sentrinization sites in PML . J. Biol. Chem. 273, 26675? 26682 (1998).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Duprez, E. et al. SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localization. J. Cell Sci. 112, 381?393 (1999).

    CAS  PubMed  Google Scholar 

  44. 44

    Everett, R. D. et al. The disruption of ND10 during herpes simplex virus infection correlates with the Vmw110- and proteasome-dependent loss of several PML isoforms . J. Virol. 72, 6581?6591 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Muller, S. & Dejean, A. Viral immediate-early proteins abrogate the modification by SUMO-1 of PML and Sp100 proteins, correlating with nuclear body disruption. J. Virol. 73, 5137? 5143 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Everett, R. D., Lomonte, P., Sternsdorf, T., van Driel, R. & Orr, A. Cell cycle regulation of PML modification and ND10 composition. J. Cell Sci. 112, 4581?4588 (1999).

    CAS  PubMed  Google Scholar 

  47. 47

    Zhong, S. et al. Role of SUMO-1-modified PML in nuclear body formation. Blood 95, 2748?2752 ( 2000).

    CAS  PubMed  Google Scholar 

  48. 48

    Ishov, A. M. et al. PML is critical for ND10 formation and recruits the PML-interacting protein Daxx to this nuclear structure when modified by SUMO-1. J. Cell Biol. 147, 221?234 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Li, H. et al. Sequestration and inhibition of Daxx-mediated transcriptional repression by PML. Mol. Cell. Biol. 20, 1784? 1796 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50

    Lehembre, F., Muller, S., Pandolfi, P. P. & Dejean, A. Regulation of Pax3 transcriptional activity by SUMO-1-modified PML. Oncogene 20, 1?9 ( 2001).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Pearson, M. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207? 210 (2000).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Gostissa, M. et al. Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J. 18, 6462? 6471 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Rodriguez, M. S. et al. SUMO-1 modification activates the transcriptional response of p53. EMBO J. 18, 6455? 6461 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Muller, S. et al. c-Jun and p53 activity is modulated by SUMO-1 modification . J. Biol. Chem. 275, 13321? 13329 (2000).

    CAS  PubMed  Article  Google Scholar 

  55. 55

    Minty, A., Dumont, X., Kaghad, M. & Caput, D. Covalent modification of p73α by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif. J. Biol. Chem. 275, 36316?36323 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Seeler, J. S., Marchio, A., Sitterlin, D., Transy, C. & Dejean, A. Interaction of SP100 with HP1 proteins: a link between the promyelocytic leukemia-associated nuclear bodies and the chromatin compartment. Proc. Natl Acad. Sci. USA 95 , 7316?7321 (1998).

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Lehming, N., Le Saux, A., Schuller, J. & Ptashne, M. Chromatin components as part of a putative transcriptional repressing complex . Proc. Natl Acad. Sci. USA 95, 7322? 7326 (1998).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Sternsdorf, T., Jensen, K., Reich, B. & Will, H. The nuclear dot protein SP100, characterization of domains necessary for dimerization, subcellular localization, and modification by small ubiquitin-like modifiers. J. Biol. Chem. 274, 12555?12566 (1999).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Seeler, J. S. et al. Common properties of the nuclear body protein SP100 and the TIF1α chromatin factor: the role of SUMO modification. Mol. Cell. Biol. (in the press).

  60. 60

    Kim, Y. H., Choi, C. Y. & Kim, Y. Covalent modification of the homeodomain-interacting protein kinase 2 (HIPK2) by the ubiquitin-like protein SUMO-1. Proc. Natl Acad. Sci. USA 96, 12350?12355 (1999).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Chakrabarti, S. R., Sood, R., Nandi, S. & Nucifora, G. Posttranslational modification of TEL and TEL/AML1 by SUMO-1 and cell-cycle-dependent assembly into nuclear bodies. Proc. Natl Acad. Sci. USA 97, 13281?13285 (2000).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Chakrabarti, S. R. et al. Modulation of TEL transcription activity by interaction with the ubiquitin-conjugating enzyme UBC9. Proc. Natl Acad. Sci. USA 96, 7467?7472 ( 1999).

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Poukka, H., Karvonen, U., Janne, O. A. & Palvimo, J. J. Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1). Proc. Natl Acad. Sci. USA 97, 14145?14150 (2000).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Lehembre, F. et al. Covalent modification of the transcriptional repressor tramtrack by the ubiquitin-related protein Smt3 in Drosophila flies. Mol. Cell. Biol. 20, 1072?1082 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Desterro, J. M., Rodriguez, M. S. & Hay, R. T. SUMO-1 modification of IκBα inhibits NF-κB activation. Mol. Cell 2, 233 ?239 (1998).This report identifies IκBα as a target for SUMO and provides evidence for a role of sumoylation in counteracting the ubiquitylation of IκBα, thus leading to the model that SUMO acts as a protein stabilizer.

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Buschmann, T., Fuchs, S. Y., Lee, C. G., Pan, Z. Q. & Ronai, Z. SUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53. Cell 101, 753?762 (2000). This study reports that SUMO and ubiquitin share an identical lysine residue within the RING finger of Mdm2 and suggest that sumoylation stabilizes Mdm2.

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Israel, A. The IKK complex: an integrator of all signals that activate NF-κB? Trends Cell Biol. 10, 129?133 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68

    Bhaskar, V., Valentine, S. A. & Courey, A. J. A functional interaction between dorsal and components of the Smt3 conjugation machinery. J. Biol. Chem. 275 , 4033?4040 (2000).

    CAS  PubMed  Article  Google Scholar 

  69. 69

    Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H. & Weissman, A. M. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J. Biol. Chem. 275, 8945?8951 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70

    Honda, R. & Yasuda, H. Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase . Oncogene 19, 1473?1476 (2000).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Melchior, F. & Hengst, L. Mdm2?SUMO1: is bigger better? Nature Cell Biol. 2, E161? E163 (2000).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    al-Khodairy, F., Enoch, T., Hagan, I. M. & Carr, A. M. The Schizosaccharomyces pombe hus5 gene encodes a ubiquitin conjugating enzyme required for normal mitosis. J. Cell Sci. 108, 475? 486 (1995).

    CAS  PubMed  Google Scholar 

  73. 73

    Seufert, W., Futcher, B. & Jentsch, S. Role of a ubiquitin-conjugating enzyme in degradation of S- and M-phase cyclins. Nature 373, 78 ?81 (1995).

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Takahashi, Y. et al. Smt3, a SUMO-1 homolog, is conjugated to Cdc3, a component of septin rings at the mother-bud neck in budding yeast. Biochem. Biophys. Res. Commun. 259, 582?587 (1999).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Johnson, E. S. & Blobel, G. Cell cycle-regulated attachment of the ubiquitin-related protein SUMO to the yeast septins. J. Cell Biol. 147, 981?994 (1999).This comprehensive study identifies septins as the major substrates for SUMO in yeast and suggests a role of septin sumoylation in cytokinesis.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76

    Meluh, P. B. & Koshland, D. Evidence that the MIF2 gene of Saccharomyces cerevisiae encodes a centromere protein with homology to the mammalian centromere protein CENP-C. Mol. Biol. Cell 6, 793?807 (1995). This work initially identifies the yeast SMT3 gene among other genes as a suppressor of MIF2 mutations, suggesting a role of SUMO for the maintenance of genomic integrity.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77

    Brown, M. T., Goetsch, L. & Hartwell, L. H. MIF2 is required for mitotic spindle integrity during anaphase spindle elongation in Saccharomyces cerevisiae. J. Cell Biol. 123, 387?403 (1993).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Tanaka, K. et al. Characterization of a fission yeast SUMO-1 homologue, pmt3p, required for multiple nuclear events, including the control of telomere length and chromosome segregation. Mol. Cell. Biol. 19, 8660?8672 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    Shen, Z., Pardington-Purtymun, P. E., Comeaux, J. C., Moyzis, R. K. & Chen, D. J. UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins. Genomics 36, 271?279 (1996).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Shen, Z., Pardington-Purtymun, P. E., Comeaux, J. C., Moyzis, R. K. & Chen, D. J. Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system. Genomics 37, 183?186 ( 1996).

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Kovalenko, O. V. et al. Mammalian ubiquitin-conjugating enzyme Ubc9 interacts with Rad51 recombination protein and localizes in synaptonemal complexes. Proc. Natl Acad. Sci. USA 93, 2598? 2563 (1996).

    Article  Google Scholar 

  82. 82

    Li, W. et al. Regulation of double-strand break-induced mammalian homologous recombination by UBL1, a RAD51-interacting protein. Nucleic Acids Res. 28, 1145?1153 ( 2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83

    Mao, Y., Sun, M., Desai, S. D. & Liu, L. F. SUMO-1 conjugation to topoisomerase I: a possible repair response to topoisomerase-mediated DNA damage. Proc. Natl Acad. Sci. USA 97, 4046 ?4051 (2000).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Mao, Y., Desai, S. D. & Liu, L. F. SUMO-1 conjugation to human DNA topoisomerase II isozymes . J. Biol. Chem. 275, 26066? 26073 (2000).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Kawabe, Y. et al. Covalent modification of the Werner's syndrome gene product with the ubiquitin-related protein, SUMO-1. J. Biol. Chem. 275, 20963?20966 (2000).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Yeager, T. R. et al. Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res. 59, 4175?4179 (1999).

    CAS  PubMed  Google Scholar 

  87. 87

    Zhong, S. et al. A role for PML and the nuclear body in genomic stability. Oncogene 18, 7941?7947 ( 1999).

    CAS  PubMed  Article  Google Scholar 

  88. 88

    Johnson, F. B. et al. Association of the Bloom syndrome protein with topoisomerase IIIα in somatic and meiotic cells. Cancer Res. 60, 1162?1167 (2000).

    CAS  PubMed  Google Scholar 

  89. 89

    Everett, R. D. et al. A dynamic connection between centromeres and ND10 proteins . J. Cell Sci. 112, 3443? 3454 (1999).

    CAS  PubMed  Google Scholar 

  90. 90

    Everett, R. D. ICP0 induces the accumulation of colocalizing conjugated ubiquitin. J. Virol. 74, 9994?10005 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91

    Zhong, S., Salomoni, P. & Pandolfi, P. P. The transcriptional role of PML and the nuclear body . Nature Cell Biol. 2, E85? E90 (2000).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Seeler, J. S. & Dejean, A. The PML nuclear bodies: actors or extras? Curr. Opin. Genet. Dev. 9, 362? 367 (1999).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Hofmann, H., Floss, S. & Stamminger, T. Covalent modification of the transactivator protein IE2-p86 of human cytomegalovirus by conjugation to the ubiquitin-homologous proteins SUMO-1 and hSMT3b. J. Virol. 74, 2510?2524 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94

    Adamson, A. L. & Kenney, S. The epstein-barr virus immediate-early protein BZLF1 is SUMO?1 modified and disrupts promyelocytic leukemia (PML) bodies. J. Virol. 74, 1224?1233 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95

    Zhang, Q., Gutsch, D. & Kenney, S. Functional and physical interaction between p53 and BZLF1: implications for Epstein-Barr virus latency. Mol. Cell. Biol. 14, 1929?1938 ( 1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96

    Andres, G., Alejo, A., Simon-Mateo, C. & Salas, M. L. African swine fever virus protease: A new viral member of the SUMO-1?specific protease family. J. Biol. Chem. 276, 780 ?787 (2000).

    Article  Google Scholar 

  97. 97

    Orth, K. et al. Disruption of signaling by yersinia effector YopJ, a ubiquitin-like protein protease. Science 290, 1594? 1597 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98

    Saitoh, H. et al. Ubc9p and the conjugation of SUMO-1 to RanGAP1 and RanBP2 . Curr. Biol. 8, 121?124 (1998).

    CAS  PubMed  Article  Google Scholar 

  99. 99

    Giorgino, F. et al. The sentrin-conjugating enzyme mUbc9 interacts with GLUT4 and GLUT1 glucose transporters and regulates transporter levels in skeletal muscle cells. Proc. Natl Acad. Sci. USA 97, 1125?1130 (2000).

    CAS  PubMed  Article  Google Scholar 

  100. 100

    Long, X. & Griffith, L. C. Identification and characterization of a SUMO?1 conjugation system that modifies neuronal CaMKII in Drosophila melanogaster. J. Biol. Chem. 275, 40765?40776 (2000).

    CAS  Google Scholar 

  101. 101

    Rangasamy, D., Woytek, K., Khan, S. A. & Wilson, V. G. SUMO?1 modification of bovine papillomavirus E1 protein is required for intranuclear accumulation. J. Biol. Chem. 275, 37999? 38004(2000).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

We wish to thank C. D. Lima for the permission to include the structural data on ULP1-SMT3 in this review and we are indebted to many colleagues for sharing unpublished results. S. M. would like to express his special thanks to Anne Dejean for stimulating discussions, encouragement and continuous support during his stay in her laboratory.

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DATABASE LINKS

ubiquitin

RUB1

Apg8

Apg12

parkin

RAD23

DSK2

SMT3

SUMO-1

SUMO-2

SUMO-3

RanGAP1

AOS1

UBA2

UBA1

UBC9

UBC4

UBC7

ULP1

ULP2

SMT3IP1

SENP-1

SUSP-1

Ran

RanBP2

RNA1

semushi

PML

p53

Daxx

p73

Sp100

HP1

HIPK2

TEL

c-Jun

androgen receptor

Tramtrack 69

NF-κB

Mdm2

IκBα

TNF

Dorsal

Cactus

RING finger

CDC3

CDC11

SEP7

MIF2

RAD51

RAD52

DNA topisomerase I

DNA topoisomerase II

RecQ

BLM

CENP-C

FURTHER INFORMATION

Jentsch lab

ENCYCLOPEDIA OF LIFE SCIENCES

Nuclear?cytoplasmic transport

Ubiquitin pathway

Glossary

ISOPEPTIDE BOND

Any amide bond formed between a carboxyl group of one amino acid and an amino group of another where either group occupies a position other than α.

26S PROTEASOME

Large multisubunit protease complex that selectively degrades multi-ubiquitylated proteins. It contains a 20S particle that carries the catalytic activity and two regulatory 19S particles.

CYSTEINE PROTEASE

Protease that has a cysteine at the active site.

SUMO CONJUGATE PATTERN

Pattern of bands corresponding to sumoylated substrates detectable on an immunoblot with an anti-SUMO antibody.

EST

DNA sequence obtained by sequencing an end of a random complementary DNA clone from a cDNA library.

NUCLEAR PORE COMPLEX

Large multiprotein complex that forms a channel in the nuclear envelope of an eukaryotic cell, joining the inner and outer nuclear membranes and allowing transport of proteins to and from the nucleus.

BICOID

A segment polarity protein, discovered in Drosophila, that provides positional cues for the development of head and thoracic segments.

PML NUCLEAR BODIES

One type of nuclear speckles of unknown function that contains several proteins, including the promyelocytic leukaemia protein PML. PML nuclear bodies are also called PODs (PML oncogenic domains) or ND10 (nuclear dots 10).

RING-FINGER PROTEINS

A family of proteins structurally defined by the presence of the zinc-binding RING-finger motif. The RING consensus sequence is: CX2CX(9?39)CX(1?3)HX(2?3)C/HX2CX(4?48)CX2C. The cysteines and histidines represent metal binding sites. The first, second, fifth and sixth of these bind one zinc ion and the third, fourth, seventh and eighth bind the second.

HP1 FAMILY

(Heterochromatin protein 1 family). A family of chromosomal non-histone proteins primarily associated with heterochromatin. HP1 proteins have been implicated in gene regulation, DNA replication and nuclear architecture.

HMG1/2 FAMILY

(High-mobility group 1/2 ). Large protein family of small non-histone components of chromatin that function in higher-order chromatin structure.

HOMEODOMAIN TRANSCRIPTION FACTORS

Transcription factors with a 60-amino-acid DNA-binding domain comprised of three α-helices.

ETS

Proto-oncogene family related to v-ets, one of the oncogenes of the acutely transforming avian erythroblastosis virus E26.

POLYTENE CHROMOSOME

A giant chromosome formed by many replications of the DNA. The replicated DNA molecules tightly align side-by-side in parallel register, creating a non-mitotic chromosome that is visible by light microscopy.

IκBα

Inhibitory subunit of the NF-κB transcription factor, which is phosphorylated, ubiquitylated and degraded in response to activating stimuli.

MITOTIC SPINDLE

A highly dynamic bipolar array of microtubules that forms during mitosis or meiosis and serves to move the duplicated chromosomes apart.

SEPTINS

Highly conserved protein family first identified in yeast and more recently found in a wide range of animal cells. They are thought to function primarily in the control of cytokinesis, where they form a 10-nm filamentous ring that encircles the yeast bud neck.

HIGH-COPY SUPPRESSOR

Gene that suppresses a phenotype when expressed at high copy number.

CENTROMERE

Region of a chromosome that is attached to the spindle during nuclear division.

MINICHROMOSOME

An extrachromosomal plasmid DNA that contains a chromosomal origin of replication.

SYNAPTONEMAL COMPLEX

Structure that holds paired chromosomes together during prophase I of meiosis and that promotes genetic recombination.

WERNER SYNDROME

A rare autosomal recessive disorder, characterized by the early development of various age-related diseases. The gene responsible for Werner syndrome (WRN) encodes a DNA helicase homologous to Escherichia coli RecQ.

BLOOM SYNDROME

A rare cancer-predisposing autosomal recessive disorder characterized by genomic instability, immunodeficiency and small stature. BLM, the gene mutated in Bloom syndrome, encodes a DNA helicase of the RecQ family.

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Müller, S., Hoege, C., Pyrowolakis, G. et al. Sumo, ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol 2, 202–210 (2001). https://doi.org/10.1038/35056591

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