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  • Review Article
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Nuclear and unclear functions of SUMO

Key Points

  • The covalent attachment of the ubiquitin-like SUMO (small ubiquitin-like modifier) protein (sumoylation) to target proteins involves a pathway that is ana

  • logous to ubiquitylation, with E1 (activating), E2 (conjugating), E3 (ligase) and SUMO protease enzymes.

  • Recent progress in the study of the SUMO pathway has revealed the existence of at least three protein types (Siz/PIAS (Sap and Miz/protein inhibitors of activated STAT), RanBP2 (Ran binding-protein 2) and Pc2 (Polycomb 2)) that function as SUMO E3 ligases. Although attractive, the idea that these proteins suffice to regulate, for example, SUMO substrate specificity, is probably too simple. Rather, it is more plausible that sumoylation, like ubiquitylation, requires larger multiprotein complexes to achieve specific modification and biological activity in vivo.

  • Two principal rationales for sumoylation have been invoked classically. The first, exemplified by the case of the nuclear import factor RanGAP1 (Ran GTPase-activating protein 1), implicates sumoylation in the re-targeting of a protein from one cellular compartment to another. The second, exemplified by IκBα and proliferating cell nuclear antigen (PCNA), proposes that sumoylation regulates other modifications (for example, ubiquitylation) by competing for the same attachment site on the substrate.

  • Most studied examples support SUMO's role in protein targeting, either by regulating nuclear import or export, or by re-localizing modified substrates to specific subnuclear structures such as the promyelocytic leukaemia (PML) nuclear bodies.

  • Sumoylation has important roles in gene regulation, where, more often than not, it is associated with repression (or attenuation) of transcription. Frequently, this effect is associated with the re-targeting of transcription factors or cofactors to specific subnuclear domains. However, a specific role for sumoylation at the promoter cannot be ruled out.

  • Genetic and biochemical approaches have also shown sumoylation to be involved in DNA repair, recombination and chromosome dynamics, therefore pointing to important and evolutionarily conserved functions in the maintenance of genomic integrity.

  • Sumoylation is a dynamic, reversible process. Moreover, many of the known SUMO substrates have been previously shown to interact with each other, or to occur in the same protein complexes. Therefore, a more complete understanding of SUMO's biological roles will require describing the activity of SUMO substrates and pathway components in the context of the multiprotein complexes that contain them.

Abstract

Post-translational modification by the ubiquitin-like SUMO protein is emerging as a defining feature of eukaryotic cells. Sumoylation has crucial roles in the regulatory challenges that face nucleate cells, including the control of nucleocytoplasmic signalling and transport and the faithful replication of a large and complex genome, as well as the regulation of gene expression.

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Figure 1: The SUMO pathway.
Figure 2: SUMO substrates grouped by function.
Figure 3: Sumoylation and nuclear import.

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References

  1. Hicke, L. Protein regulation by monoubiquitin. Nature Rev. Mol. Cell Biol. 2, 195–201 (2001).

    CAS  Google Scholar 

  2. 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).

    CAS  PubMed  Google Scholar 

  3. 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).

    CAS  PubMed  Google Scholar 

  4. 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  Google Scholar 

  5. 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  Google Scholar 

  6. Desterro, J. M., Rodriguez, M. S. & Hay, R. T. SUMO-1 modification of IκBα inhibits NF-κB activation. Mol. Cell 2, 233–239 (1998). The classic — and so far only — example of how sumoylation prevents proteasomal protein degradation by targeting the same acceptor lysine as ubiquitylation.

    CAS  PubMed  Google Scholar 

  7. Melchior, F. SUMO—nonclassical, ubiquitin. Annu. Rev. Cell Dev. Biol. 16, 591–626 (2000).

    CAS  PubMed  Google Scholar 

  8. Müller, S., Hoege, C., Pyrowolakis, G. & Jentsch, S. SUMO, ubiquitin's mysterious cousin. Nature Rev. Mol. Cell. Biol. 2, 202–210 (2001).

    Google Scholar 

  9. Seeler, J. S. & Dejean, A. SUMO: of branched proteins and nuclear bodies. Oncogene 20, 7243–7249 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Jin, C., Shiyanova, T., Shen, Z. & Liao, X. Heteronuclear nuclear magnetic resonance assignments, structure and dynamics of SUMO-1, a human ubiquitin-like protein. Int. J. Biol. Macromol. 28, 227–234 (2001).

    CAS  PubMed  Google Scholar 

  12. Sheng, W. & Liao, X. Solution structure of a yeast ubiquitin-like protein Smt3: the role of structurally less defined sequences in protein-protein recognitions. Protein Sci. 11, 1482–1491 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kurepa, J. et al. The SUMO protein modification system in Arabidopsis: accumulation of SUMO1 and 2 conjugates is increased by stress. J. Biol. Chem. 278, 6862–6872 (2002).

    PubMed  Google Scholar 

  14. Saitoh, H. & Hinchey, J. Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J. Biol. Chem. 275, 6252–6258 (2000).

    CAS  PubMed  Google Scholar 

  15. Tatham, M. H. et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J. Biol. Chem. 276, 35368–35374 (2001).

    CAS  PubMed  Google Scholar 

  16. Pichler, A., Gast, A., Seeler, J. S., Dejean, A. & Melchior, F. The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108, 109–120 (2002). This report shows that the nucleoporin RanBP2 (Nup358), which is located at the cytoplasmic filaments of the nuclear pore complex, is itself highly sumoylated (forming poly-SUMO chains) and has SUMO E3 ligase activity for the modification of the PML nuclear-body protein SP100.

    CAS  PubMed  Google Scholar 

  17. Johnson, E. S. & Gupta, A. A. An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 106, 735–744 (2001). This report, and also reference 21, shows that Siz1, a yeast homologue of the mammalian PIAS proteins, is a SUMO E3 ligase for many cellular proteins, notably the yeast septins.

    CAS  PubMed  Google Scholar 

  18. Ho, J. C. & Watts, F. Z. Characterization of SUMO conjugating enzyme mutants in Schizosaccharomyces pombe identifies a dominant negative allele which severely reduces SUMO conjugation. Biochem. J. 372, 97–102 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Li, Y. et al. Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc. Natl Acad. Sci. USA 100, 259–264 (2003).

    CAS  PubMed  Google Scholar 

  20. Jackson, P. K. A new RING for SUMO: wrestling transcriptional responses into nuclear bodies with PIAS family E3 SUMO ligases. Genes Dev. 15, 3053–3058 (2001). In this short review on the characterization of Siz/PIAS proteins as SUMO E3 ligases, the author makes a similar argument for the 'Zen' concept, using phosphorylation as an example.

    CAS  PubMed  Google Scholar 

  21. Takahashi, Y., Kahyo, T., Toh, E. A., Yasuda, H. & Kikuchi, Y. Yeast Ull1/Siz1 is a novel SUMO1/Smt3 ligase for septin components and functions as an adaptor between conjugating enzyme and substrates. J. Biol. Chem. 276, 48973–48977 (2001).

    CAS  PubMed  Google Scholar 

  22. Kahyo, T., Nishida, T. & Yasuda, H. Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol. Cell 8, 713–718 (2001). The first report that extends the findings in yeast, reported in references 17 and 21, to show that the mammalian PIAS1 has SUMO E3 ligase activity for p53.

    CAS  PubMed  Google Scholar 

  23. Schmidt, D. & Müller, S. Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc. Natl Acad. Sci. USA 99, 2872–2877 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Sachdev, S. et al. PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15, 3088–3103 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kotaja, N., Karvonen, U., Janne, O. A. & Palvimo, J. J. PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Mol. Cell. Biol. 22, 5222–5234 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hochstrasser, M. SP-RING for SUMO: new functions bloom for a ubiquitin-like protein. Cell 107, 5–8 (2001).

    CAS  PubMed  Google Scholar 

  27. Kirsh, O. et al. The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J. 21, 2682–2691 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Miyauchi, Y., Yogosawa, S., Honda, R., Nishida, T. & Yasuda, H. Sumoylation of Mdm2 by PIAS and RanBP2 enzymes. J. Biol. Chem. 18, 50131–50136 (2002).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  30. Kagey, M. H., Melhuish, T. A. & Wotton, D. The Polycomb protein Pc2 is a SUMO E3. Cell 113, 127–137 (2003).

    CAS  PubMed  Google Scholar 

  31. Joazeiro, C. A. & Weissman, A. M. RING finger proteins: mediators of ubiquitin ligase activity. Cell 102, 549–552 (2000).

    CAS  PubMed  Google Scholar 

  32. Li, S. J. & Hochstrasser, M. A new protease required for cell-cycle progression in yeast. Nature 398, 246–251 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  34. Okuma, T., Honda, R., Ichikawa, G., Tsumagari, N. & Yasuda, H. In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2. Biochem. Biophys. Res. Commun. 254, 693–698 (1999).

    CAS  PubMed  Google Scholar 

  35. Nishida, T. & Yasuda, H. PIAS1 and PIASxa function as SUMO-E3 ligases toward androgen receptor, and repress androgen receptor-dependent transcription. J. Biol. Chem. 9, 41311–41317 (2002).

    Google Scholar 

  36. 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 

  37. Hietakangas, V. et al. Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Mol. Cell. Biol. 23, 2953–2968 (2003). The phosphorylation of a specific serine residue of HSF1 precedes sumoylation, thereby providing an excellent example for the interplay between two types of post-translational modification in regulating the activity of a substrate.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sobko, A., Ma, H. & Firtel, R. A. Regulated SUMOylation and ubiquitination of DdMEK1 is required for proper chemotaxis. Dev. Cell 2, 745–756 (2002). This in-depth study of Mek1 signalling in the slime mold Dictyostelium provides important information on the role of sumoylation in nuclear export and on its interplay with other modifications, notably phosphorylation and ubiquitylation.

    CAS  PubMed  Google Scholar 

  39. Rodriguez, M. S., Dargemont, C. & Hay, R. T. SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J. Biol. Chem. 276, 12654–12659 (2001).

    CAS  PubMed  Google Scholar 

  40. 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  PubMed  Google Scholar 

  41. Pichler, A. & Melchior, F. Ubiquitin-related modifier SUMO1 and nucleocytoplasmic transport. Traffic 3, 381–387 (2002).

    CAS  PubMed  Google Scholar 

  42. Stade, K. et al. A lack of SUMO conjugation affects cNLS-dependent nuclear protein import in yeast. J. Biol. Chem. 18, 49554–49561 (2002).

    Google Scholar 

  43. Joseph, J., Tan, S. H., Karpova, T. S., McNally, J. G. & Dasso, M. SUMO-1 targets RanGAP1 to kinetochores and mitotic spindles. J. Cell Biol. 156, 595–602 (2002). Shows that sumoylation is required, not only for the interphasic targeting of the nuclear import factor RanGAP1 to the nuclear pores, but also for RanGAP1 targeting to kinetochores and mitotic spindles during mitosis, where it co-localizes with RanBP2.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Endter, C., Kzhyshkowska, J., Stauber, R. & Dobner, T. SUMO-1 modification required for transformation by adenovirus type 5 early region 1B 55-kDa oncoprotein. Proc. Natl Acad. Sci. USA 98, 11312–11317 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Kwek, S. S., Derry, J., Tyner, A. L., Shen, Z. & Gudkov, A. V. Functional analysis and intracellular localization of p53 modified by SUMO-1. Oncogene 20, 2587–2599 (2001).

    CAS  PubMed  Google Scholar 

  46. Ross, S., Best, J. L., Zon, L. I. & Gill, G. SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization. Mol. Cell 10, 831–842 (2002).

    CAS  PubMed  Google Scholar 

  47. Sapetschnig, A. et al. Transcription factor Sp3 is silenced through SUMO modification by PIAS1. EMBO J. 21, 5206–5215 (2002). This paper and reference 46 illustrate a now almost prototypical example in which sumoylation is shown to be required for the function of a transcriptional repression domain.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Goodson, M. L. et al. SUMO-1 modification regulates the DNA-binding activity of heat shock transcription factor 2 (HSF2), a PML nuclear body associated transcription factor. J. Biol. Chem. 276, 18513–18518 (2001).

    CAS  PubMed  Google Scholar 

  49. Hong, Y. et al. Regulation of heat shock transcription factor 1 by stress-induced SUMO- 1 modification. J. Biol. Chem. 276, 40263–40267 (2001).

    CAS  PubMed  Google Scholar 

  50. 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  PubMed Central  Google Scholar 

  51. Wood, L. D., Irvin, B. J., Nucifora, G., Luce, K. S. & Hiebert, S. W. Small ubiquitin-like modifier conjugation regulates nuclear export of TEL, a putative tumor suppressor. Proc. Natl Acad. Sci. USA 100, 3257–3262 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 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  Google Scholar 

  53. Bhaskar, V., Smith, M. & Courey, A. J. Conjugation of Smt3 to dorsal may potentiate the Drosophila immune response. Mol. Cell. Biol. 22, 492–504 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  56. Kishi, A., Nakamura, T., Nishio, Y., Maegawa, H. & Kashiwagi, A. Sumoylation of Pdx1 is associated with its nuclear localization and insulin gene activation. Am. J. Physiol. Endocrinol. Metab. 284, E830–E840 (2003).

    CAS  PubMed  Google Scholar 

  57. Tojo, M. et al. The aryl hydrocarbon receptor nuclear transporter is modulated by the SUMO-1 conjugating system. J. Biol. Chem. 277, 46576–46585 (2002).

    CAS  PubMed  Google Scholar 

  58. 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  PubMed Central  Google Scholar 

  59. Tian, S., Poukka, H., Palvimo, J. J. & Janne, O. A. SUMO-1 modification of the glucocorticoid receptor. Biochem. J. 29, 907–911 (2002).

    Google Scholar 

  60. Abdel-Hafiz, H., Takimoto, G. S., Tung, L. & Horwitz, K. B. The inhibitory function in human progesterone receptor N termini binds SUMO-1 protein to regulate autoinhibition and transrepression. J. Biol. Chem. 277, 33950–33956 (2002).

    CAS  PubMed  Google Scholar 

  61. Chauchereau, A., Amazit, L., Quesne, M., Guiochon-Mantel, A. & Milgrom, E. Sumoylation of the progesterone receptor and of the coactivator SRC-1. J. Biol. Chem. 278, 12335–12343 (2003).

    CAS  PubMed  Google Scholar 

  62. Bies, J., Markus, J. & Wolff, L. Covalent attachment of the SUMO-1 protein to the negative regulatory domain of the c-Myb transcription factor modifies its stability and transactivation capacity. J. Biol. Chem. 277, 8999–9009 (2002).

    CAS  PubMed  Google Scholar 

  63. Kim, J., Cantwell, C. A., Johnson, P. F., Pfarr, C. M. & Williams, S. C. Transcriptional activity of CCAAT/enhancer-binding proteins is controlled by a conserved inhibitory domain that is a target for sumoylation. J. Biol. Chem. 277, 38037–38044 (2002).

    CAS  PubMed  Google Scholar 

  64. Hirano, Y., Murata, S., Tanaka, K., Shimizu, M. & Sato, R. SREBPs are negatively regulated through SUMO-1 modification independent of the ubiquitin/26S proteasome pathway. J. Biol. Chem. 278, 16809–16819 (2003).

    CAS  PubMed  Google Scholar 

  65. Eloranta, J. J. & Hurst, H. C. Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo. J. Biol. Chem. 277, 30798–30804 (2002).

    CAS  PubMed  Google Scholar 

  66. Nakagawa, K. & Yokosawa, H. PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1. FEBS Lett. 530, 204–208 (2002).

    CAS  PubMed  Google Scholar 

  67. Iniguez-Lluhi, J. A. & Pearce, D. A common motif within the negative regulatory regions of multiple factors inhibits their transcriptional synergy. Mol. Cell. Biol. 20, 6040–6050 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Courey, A. J. Cooperativity in transcriptional control. Curr. Biol. 11, R250–R252 (2001).

    CAS  PubMed  Google Scholar 

  69. Verger, A., Perdomo, J. & Crossley, M. Modification with SUMO. EMBO Rep. 4, 137–142 (2003). A timely review outlining SUMO's effects on transcription.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Subramanian, L., Benson, M. D. & Iniguez-Lluhi, J. A. A synergy control motif within the attenuator domain of C/EBPα inhibits transcriptional synergy through its PIASy-enhanced modification by SUMO-1 or SUMO-3. J. Biol. Chem. 278, 9134–9141 (2003).

    CAS  PubMed  Google Scholar 

  71. Le Drean, Y., Mincheneau, N., Le Goff, P. & Michel, D. Potentiation of glucocorticoid receptor transcriptional activity by sumoylation. Endocrinology 143, 3482–3489 (2002).

    CAS  PubMed  Google Scholar 

  72. Kotaja, N., Karvonen, U., Janne, O. A. & Palvimo, J. J. The nuclear receptor interaction domain of GRIP1 is modulated by covalent attachment of SUMO-1. J. Biol. Chem. 277, 30283–30288 (2002).

    CAS  PubMed  Google Scholar 

  73. Colombo, R., Boggio, R., Seiser, C., Draetta, G. F. & Chiocca, S. The adenovirus protein Gam1 interferes with sumoylation of histone deacetylase 1. EMBO Rep. 3, 1062–1068 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. David, G., Neptune, M. A. & DePinho, R. A. SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities. J. Biol. Chem. 277, 23658–23663 (2002).

    CAS  PubMed  Google Scholar 

  75. Girdwood, D. et al. p300 transcriptional repression is mediated by SUMO modification. Mol. Cell 11, 1043–1054 (2003). The p300 protein, normally considered as a coactivator, has a repressor domain, the function of which is shown here to rely on the sumoylation-dependent recruitment of the HDAC6 histone deacetylase. Localization studies also indicate that SUMO-mediated transcriptional regulation could occur at the promoter level and not by sequestration into particular subnuclear domains.

    CAS  PubMed  Google Scholar 

  76. Chung, C. D. et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science 278, 1803–1805 (1997).

    CAS  PubMed  Google Scholar 

  77. Liu, B. et al. Inhibition of Stat1-mediated gene activation by PIAS1. Proc. Natl Acad. Sci. USA 95, 10626–10631 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kotaja, N., Aittomaki, S., Silvennoinen, O., Palvimo, J. J. & Janne, O. A. ARIP3 (androgen receptor-interacting protein 3) and other PIAS (protein inhibitor of activated STAT) proteins differ in their ability to modulate steroid receptor-dependent transcriptional activation. Mol. Endocrinol. 14, 1986–2000 (2000).

    CAS  PubMed  Google Scholar 

  79. Tussie-Luna, M. I., Bayarsaihan, D., Seto, E., Ruddle, F. H. & Roy, A. L. Physical and functional interactions of histone deacetylase 3 with TFII-I family proteins and PIASxβ. Proc. Natl Acad. Sci. USA 99, 12807–12812 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kotaja, N., Vihinen, M., Palvimo, J. J. & Janne, O. A. Androgen receptor-interacting protein 3 and other PIAS proteins cooperate with glucocorticoid receptor-interacting protein 1 in steroid receptor-dependent signaling. J. Biol. Chem. 277, 17781–17788 (2002).

    CAS  PubMed  Google Scholar 

  81. Takahashi, K. et al. DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx α to the receptor. J. Biol. Chem. 276, 37556–37563 (2001).

    CAS  PubMed  Google Scholar 

  82. Megidish, T., Xu, J. H. & Xu, C. W. Activation of p53 by protein inhibitor of activated Stat1 (PIAS1). J. Biol. Chem. 277, 8255–8259 (2002).

    CAS  PubMed  Google Scholar 

  83. Hahn, S. L., Wasylyk, B., Criqui-Filipe, P. & Criqui, P. Modulation of ETS-1 transcriptional activity by huUBC9, a ubiquitin-conjugating enzyme. Oncogene 15, 1489–1495 (1997).

    CAS  PubMed  Google Scholar 

  84. 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  PubMed Central  Google Scholar 

  85. Poukka, H., Aarnisalo, P., Karvonen, U., Palvimo, J. J. & Janne, O. A. Ubc9 interacts with the androgen receptor and activates receptor-dependent transcription. J. Biol. Chem. 274, 19441–19446 (1999).

    CAS  PubMed  Google Scholar 

  86. Best, J. L. et al. SUMO-1 protease-1 regulates gene transcription through PML. Mol. Cell 10, 843–855 (2002)

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  88. 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  PubMed Central  Google Scholar 

  89. 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  Google Scholar 

  90. Hoege, C., Pfander, B., Moldovan, G. L., Pyrowolakis, G. & Jentsch, S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419, 135–141 (2002). Describes the serendipitous discovery that sumoylation, in targeting the same lysine residue on PCNA as mono- and poly-ubiquitylation, has a role in regulating alternative DNA-repair pathways.

    CAS  PubMed  Google Scholar 

  91. Enomoto, T. Functions of RecQ family helicases: possible involvement of Bloom's and Werner's syndrome gene products in guarding genome integrity during DNA replication. J. Biochem. 129, 501–507 (2001).

    CAS  PubMed  Google Scholar 

  92. 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  Google Scholar 

  93. Suzuki, H. et al. The N-terminal internal region of BLM is required for the formation of dots/rod-like structures which are associated with SUMO-1. Biochem. Biophys. Res. Commun. 286, 322–327 (2001).

    CAS  PubMed  Google Scholar 

  94. Hardeland, U., Steinacher, R., Jiricny, J. & Schar, P. Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover. EMBO J. 21, 1456–1464 (2002). A striking demonstration of SUMO's ability to affect the activity of an enzyme, thymine DNA glycosylase, possibly by an allosteric mechanism.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 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). The demonstration that overexpression of yeast SUMO (Smt3) suppresses the phenotype of a temperature-sensitive mutation in Mif-2, the homologue of the mammalian centromere protein, CENP-C. Although unknown at the time, this is the first example of a genetic interaction between sumoylation and chromosome dynamics.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Strunnikov, A. V., Aravind, L. & Koonin, E. V. Saccharomyces cerevisiae SMT4 encodes an evolutionarily conserved protease with a role in chromosome condensation regulation. Genetics 158, 95–107 (2001). This paper, similar to reference 95 above, shows genetic interactions between sumoylation (notably by Smt4/Ulp2 and Siz1/PIAS) and the control of chromosome condensation in budding yeast.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Hari, K. L., Cook, K. R. & Karpen, G. H. The Drosophila Su(var)2-10 locus regulates chromosome structure and function and encodes a member of the PIAS protein family. Genes Dev. 15, 1334–1348 (2001). This work demonstrates that in flies, as in yeast, sumoylation might be important for chromosome structure, as mutation of the Drosophila PIAS homologue Suvar2-10/Zimp leads to defects in chromosome condensation and mitosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Biggins, S., Bhalla, N., Chang, A., Smith, D. L. & Murray, A. W. Genes involved in sister chromatid separation and segregation in the budding yeast Saccharomyces cerevisiae. Genetics 159, 453–470 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 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  Google Scholar 

  100. Shayeghi, M., Doe, C. L., Tavassoli, M. & Watts, F. Z. Characterisation of Schizosaccharomyces pombe rad31, a UBA-related gene required for DNA damage tolerance. Nucl. Acids. Res. 25, 1162–1169 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 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 

  102. 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, 2958–2963 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Apionishev, S., Malhotra, D., Raghavachari, S., Tanda, S. & Rasooly, R. S. The Drosophila UBC9 homologue lesswright mediates the disjunction of homologues in meiosis I. Genes Cells 6, 215–224 (2001).

    CAS  PubMed  Google Scholar 

  104. Bachant, J., Alcasabas, A., Blat, Y., Kleckner, N. & Elledge, S. J. The SUMO-1 isopeptidase Smt4 is linked to centromeric cohesion through SUMO-1 modification of DNA topoisomerase II. Mol. Cell 9, 1169–1182 (2002). This recent report implicates sumoylation in sister-chromatid cohesion, so providing another example of the importance of this modification in regulating chromosome dynamics.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  106. 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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  108. Everett, R. D. DNA viruses and viral proteins that interact with PML nuclear bodies. Oncogene 20, 7266–7273 (2001).

    CAS  PubMed  Google Scholar 

  109. 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  Google Scholar 

  110. Jang, M. S., Ryu, S. W. & Kim, E. Modification of Daxx by small ubiquitin-related modifier-1. Biochem. Biophys. Res. Commun. 295, 495–500 (2002).

    CAS  PubMed  Google Scholar 

  111. 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  PubMed Central  Google Scholar 

  112. Engelhardt, O. G. et al. The homeodomain-interacting kinase PKM (HIPK-2) modifies ND10 through both its kinase domain and a SUMO-1 interaction motif and alters the posttranslational modification of PML. Exp. Cell Res. 283, 36–50 (2003).

    CAS  PubMed  Google Scholar 

  113. Bischof, O. et al. Deconstructing PML-induced premature senescence. EMBO J. 21, 3358–3369 (2002). The demonstration that one specific splicing variant of the NB protein PML is sufficient to induce premature senescence when overexpressed. Interestingly, neither sumoylation of PML nor the structural integrity of the PML NBs seem necessary, thereby indicating that PML's pro-senescent activity occurs outside the PML NBs.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Gottifredi, V. & Prives, C. p53 and PML: new partners in tumor suppression. Trends Cell Biol. 11, 184–187 (2001).

    CAS  PubMed  Google Scholar 

  115. Seeler, J. S. et al. Common properties of nuclear body protein SP100 and TIF1α chromatin factor: role of SUMO modification. Mol. Cell. Biol. 21, 3314–3324 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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  Google Scholar 

  117. Taylor, D. L., Ho, J. C., Oliver, A. & Watts, F. Z. Cell-cycle-dependent localisation of Ulp1, a Schizosaccharomyces pombe Pmt3 (SUMO)-specific protease. J. Cell Sci. 115, 1113–1122 (2002).

    CAS  PubMed  Google Scholar 

  118. 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  PubMed  Google Scholar 

  119. 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  PubMed  Google Scholar 

  120. 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  Google Scholar 

  121. Hang, J. & Dasso, M. Association of the human SUMO-1 protease SENP2 with the nuclear pore. J. Biol. Chem. 277, 19961–19966 (2002).

    CAS  PubMed  Google Scholar 

  122. Kadoya, T. et al. Desumoylation activity of Axam, a novel Axin-binding protein, is involved in downregulation of β-catenin. Mol. Cell. Biol. 22, 3803–3819 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhang, H., Saitoh, H. & Matunis, M. J. Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex. Mol. Cell. Biol. 22, 6498–6508 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Nishida, T., Kaneko, F., Kitagawa, M. & Yasuda, H. Characterization of a novel mammalian SUMO-1/Smt3-specific isopeptidase, a homologue of rat axam, which is an axin-binding protein promoting β-catenin degradation. J. Biol. Chem. 276, 39060–39066 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  126. Mendoza, H. M. et al. NEDP1, a highly conserved cysteine protease that deNEDDylates Cullins. J. Biol. Chem. 278, 25637–25643 (2003).

    CAS  PubMed  Google Scholar 

  127. Wu, K. et al. DEN1 is a dual function protease capable of processing the C-terminus of Nedd8 deconjugating hyper–neddylated CUL1. J. Biol. Chem. 278, 28882–28891 (2003).

    CAS  PubMed  Google Scholar 

  128. Panse, V. G., Kuster, B., Gerstberger, T. & Hurt, E. Unconventional tethering of Ulp1 to the transport channel of the nuclear pore complex by karyopherins. Nature Cell Biol. 5, 21–27 (2003).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to our colleagues whose work could not be cited owing to space restrictions. Thanks also to F. Melchior and T. Dobner for sharing insights and unpublished observations. Research in our laboratory is supported by grants from the Association pour la Recherche sur le Cancer, the Ligue Nationale Contre le Cancer, the Association for International Cancer Research, the Fondation pour la Recherche Médicale, the European Community, the Fondation de France and the Pasteur-Negri-Weizman Council.

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DATABASES

LocusLink

Aos1

PIAS

SUMO

SUMO2

Suvar2-10

Uba1

Uba2

Ubc9

Sanger Institute: Schizosaccharomyces pombe

Hus5

Pmt3

Rad31

Swiss-Prot

CENP-C

RanBP2

SENP2

Siz1

Smt3

SUMO1

Ulp2

Glossary

SUMO

(Small ubiquitin-like modifier). Also known as PIC1 (PML interacting clone 1), GMP1 (RanGAP1 modifying protein 1), Smt3 (in budding yeast: suppressor of MIF-TWO 3), Pmt3 (in fission yeast: Pombe Smt3), Ubl1 (ubiquitin-like protein 1) and sentrin (sentry function against cell death).

RANGAP1

(Ran GTPase-activating protein 1). A nuclear import factor that binds the nucleoporin RanBP2 after SUMO modification.

ΨKXE CONSENSUS MOTIF

A short peptide consensus sequence for sumoylation, where Ψ represents a hydrophobic residue (for example, leucine, isoleucine, valine or alanine), K represents the target lysine, x represents any amino acid and E represents glutamic acid.

SIZ/PIAS PROTEIN FAMILY

(Sap and Miz/protein inhibitors of activated STAT). A conserved protein family that contains SAP and SP (Siz/PIAS)-RING-finger domains.

SAP DOMAIN

A protein domain that is characteristic of the Siz/Acinus/PIAS protein family.

RING FINGER

A C3HC4-type zinc finger, a structural derivative of which — the SP (Siz/PIAS)-RING domain — is crucial for the SUMO E3 ligase function of PIAS proteins.

NUCLEOPORIN

(Nup). The collective term for nuclear-pore-complex proteins.

RAN-BINDING PROTEIN 2

A docking protein (nucleoporin) at the cytoplasmic face of the nuclear pore complex that has been shown to be a SUMO E3 ligase. (Also known as Nup358).

IMPORTIN

A chaperone for the regulation of protein import into the nucleus.

POLYCOMB PROTEIN

A member of a diverse and conserved family (the Polycomb group, PcG) of transcriptional co-repressors that were originally isolated from Drosophila.

HECT-DOMAIN UBIQUITIN LIGASE

(HECT, homologous to E6AP carboxy-terminus). An E3 ligase that forms a ubiquitin thioester intermediate before transferring ubiquitin to the substrate.

RING-FINGER UBIQUITIN LIGASE

An E3 ligase that brings the E2-ubiquitin thioester to the substrate without forming a ubiquitin thioester intermediate.

MITOTIC SPINDLE

A microtubule-based apparatus that provides the force for chromosome separation during mitosis.

KINETOCHORE

Attachment site of mitotic spindle microtubules at the centromere.

HETEROCHROMATIN PROTEIN 1

(HP1). A member of a family of conserved proteins that were first isolated in Drosophila and that are important in transcriptional repression and in the compaction of chromatin into heterochromatin. It has recently been shown to bind methylated histone H3 through the so-called chromodomain.

NUCLEAR SPECKLE

Used as a generic term for any subnuclear domain giving a speckled (that is, non-diffuse) appearance in immunofluorescence microscopy

BASE-EXCISION REPAIR

A DNA-repair pathway that involves the removal of damaged DNA bases by DNA glycosylase enzymes.

HIGH-COPY SUPPRESSOR

A gene that, when overexpressed, suppresses the phenotype of a mutation of another gene.

CENTROMERE

The central, constricted portion of a chromosome that separates chromosome arms and is rich in heterochromatin.

CONDENSIN

A protein that is involved in pre-mitotic chromosome condensation.

SYNAPTONEMAL COMPLEX

The complex of paired homologous chromosomes and their chromatids that is present in cells undergoing meiosis (reductional division).

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Seeler, JS., Dejean, A. Nuclear and unclear functions of SUMO. Nat Rev Mol Cell Biol 4, 690–699 (2003). https://doi.org/10.1038/nrm1200

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