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Function and regulation of SUMO proteases

Nature Reviews Molecular Cell Biology volume 13, pages 755–766 (2012)Cite this article

Subjects

Key Points

  • Small ubiquitin-related modifier (SUMO) proteases control cellular mechanisms, including transcription, cell division and ribosome biogenesis. The function of SUMO proteases is to remove SUMO from SUMO-modified proteins and (for some SUMO proteases) to process precursor SUMO, which is required for the attachment of SUMO to proteins.

  • Recent studies have characterized two new classes of SUMO proteases. SUMO proteases are now known to fall into one of three distinct classes: the well-characterized UBL-specific protease (Ulp) and sentrin-specific protease (SENP) class; the desumoylating isopeptidase (DESI) class; or the ubiquitin-specific protease-like 1 (USPL1) class.

  • The known SUMO proteases have distinct substrate specificities, which are often largely controlled by the intracellular localization of the enzyme. The non-catalytic, amino-terminal regions of Ulp and SENP enzymes regulate their intracellular localization.

  • High-resolution structures of several SUMO proteases are available, and in some cases the SUMO protease is captured in a covalent, transition state-like complex with SUMO. These structures provide insights into the interactions that occur during SUMO removal from proteins and SUMO processing.

  • The localization, activity or levels of certain SUMO proteases can be modulated by environmental stimuli. For example, certain stimuli cause SENP enzyme levels to change through alterations in the transcription of particular SENP genes.

  • SUMO proteases in yeast and mammals show interesting genetic interactions with a family of enzymes called SUMO-targeted ubiquitin ligases (STUbLs), which add ubiquitin to SUMO-modified proteins. However, many questions remain about the role of SUMO proteases in the pathways that involve STUbLs, particularly the degradation of ubiquitin- and SUMO-modified STUbL substrates by the proteasome.

Abstract

Covalent attachment of small ubiquitin-like modifier (SUMO) to proteins is highly dynamic, and both SUMO–protein conjugation and cleavage can be regulated. Protein desumoylation is carried out by SUMO proteases, which control cellular mechanisms ranging from transcription and cell division to ribosome biogenesis. Recent advances include the discovery of two novel classes of SUMO proteases, insights regarding SUMO protease specificity, and revelations of previously unappreciated SUMO protease functions in several key cellular pathways. These developments, together with new connections between SUMO proteases and the recently discovered SUMO-targeted ubiquitin ligases (STUbLs), make this an exciting period to study these enzymes.

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Figure 1: SUMO conjugation and deconjugation cycle.
Figure 2: Structures of SUMO proteases.
Figure 3: Regulation of SUMO proteases.
Figure 4: The function of SENP1 in transcription during WNT signalling.
Figure 5: SUMO-targeted ubiquitin ligases.

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References

  1. Hochstrasser, M. Origin and function of ubiquitin-like proteins. Nature 458, 422–429 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Panse, V. G., Hardeland, U., Werner, T., Kuster, B. & Hurt, E. A proteome-wide approach identifies sumoylated substrate proteins in yeast. J. Biol. Chem. 279, 41346–41351 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Wohlschlegel, J. A., Johnson, E. S., Reed, S. I. & Yates, J. R. Global analysis of protein sumoylation in Saccharomyces cerevisiae. J. Biol. Chem. 279, 45662–45668 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Hannich, J. T. et al. Defining the SUMO-modified proteome by multiple approaches in Saccharomyces cerevisiae. J. Biol. Chem. 280, 4102–4110 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Wykoff, D. D. & O'Shea, E. K. Identification of sumoylated proteins by systematic immunoprecipitation of the budding yeast proteome. Mol. Cell Proteom. 4, 73–83 (2005).

    Article  CAS  Google Scholar 

  6. Elrouby, N. & Coupland, G. Proteome-wide screens for small ubiquitin-like modifier (SUMO) substrates identify Arabidopsis proteins implicated in diverse biological processes. Proc. Natl Acad. Sci. USA 107, 17415–17420 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Miller, M. J., Barrett-Wilt, G. A., Hua, Z. & Vierstra, R. D. Proteomic analyses identify a diverse array of nuclear processes affected by small ubiquitin-like modifier conjugation in Arabidopsis. Proc. Natl Acad. Sci. USA 107, 16512–16517 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Matic, I. et al. Site-specific identification of SUMO-2 targets in cells reveals an inverted SUMOylation motif and a hydrophobic cluster SUMOylation motif. Mol. Cell 39, 641–652 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Bruderer, R. et al. Purification and identification of endogenous polySUMO conjugates. EMBO Rep. 12, 142–148 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kerscher, O. SUMO junction — what's your function? New insights through SUMO-interacting motifs. EMBO Rep. 8, 550–555 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gareau, J. R. & Lima, C. D. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nature Rev. Mol. Cell Biol. 11, 861–871 (2010).

    Article  CAS  Google Scholar 

  12. Owerbach, D., McKay, E. M., Yeh, E. T., Gabbay, K. H. & Bohren, K. M. A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation. Biochem. Biophys. Res. Commun. 337, 517–520 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mukhopadhyay, D. & Dasso, M. Modification in reverse: the SUMO proteases. Trends Biochem. Sci. 32, 286–295 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Shin, E. J. et al. DeSUMOylating isopeptidase: a second class of SUMO protease. EMBO Rep. 13, 339–346 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schulz, S. et al. Ubiquitin-specific protease-like 1 (USPL1) is a SUMO isopeptidase with essential, non-catalytic functions. EMBO Rep. 13, 930–938 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Komander, D., Clague, M. J. & Urbe, S. Breaking the chains: structure and function of the deubiquitinases. Nature Rev. Mol. Cell Biol. 10, 550–563 (2009).

    Article  CAS  Google Scholar 

  21. Iyer, L. M., Koonin, E. V. & Aravind, L. Novel predicted peptidases with a potential role in the ubiquitin signaling pathway. Cell Cycle 3, 1440–1450 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Gan-Erdene, T. et al. Identification and characterization of DEN1, a deneddylase of the ULP family. J. Biol. Chem. 278, 28892–28900 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Li, S. J. & Hochstrasser, M. The Ulp1 SUMO isopeptidase: distinct domains required for viability, nuclear envelope localization, and substrate specificity. J. Cell Biol. 160, 1069–1081 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kroetz, M. B., Su, D. & Hochstrasser, M. Essential role of nuclear localization for yeast Ulp2 SUMO protease function. Mol. Biol. Cell 20, 2196–2206 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gong, L. & Yeh, E. T. Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J. Biol. Chem. 281, 15869–15877 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. Mukhopadhyay, D. et al. SUSP1 antagonizes formation of highly SUMO2/3-conjugated species. J. Cell Biol. 174, 939–949 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  PubMed  Google Scholar 

  32. Reverter, D. & Lima, C. D. A basis for SUMO protease specificity provided by analysis of human Senp2 and a Senp2–SUMO complex. Structure 12, 1519–1531 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Reverter, D. & Lima, C. D. Structural basis for SENP2 protease interactions with SUMO precursors and conjugated substrates. Nature Struct. Mol. Biol. 13, 1060–1068 (2006).

    Article  CAS  Google Scholar 

  34. Shen, L. et al. SUMO protease SENP1 induces isomerization of the scissile peptide bond. Nature Struct. Mol. Biol. 13, 1069–1077 (2006).

    Article  CAS  Google Scholar 

  35. Shen, L. N., Dong, C., Liu, H., Naismith, J. H. & Hay, R. T. The structure of SENP1–SUMO-2 complex suggests a structural basis for discrimination between SUMO paralogues during processing. Biochem. J. 397, 279–288 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang, D. T. & Schulman, B. A. Breaking up with a kinky SUMO. Nature Struct. Mol. Biol. 13, 1045–1047 (2006).

    Article  CAS  Google Scholar 

  37. Lima, C. D. & Reverter, D. Structure of the human SENP7 catalytic domain and poly-SUMO deconjugation activities for SENP6 and SENP7. J. Biol. Chem. 283, 32045–32055 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Alegre, K. O. & Reverter, D. Swapping small ubiquitin-like modifier (SUMO) isoform specificity of SUMO proteases SENP6 and SENP7. J. Biol. Chem. 286, 36142–36151 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Suh, H. Y. et al. Crystal structure of DeSI-1, a novel deSUMOylase belonging to a putative isopeptidase superfamily. Proteins 80, 2099–2104 (2012).

    CAS  PubMed  Google Scholar 

  40. Xu, Q. et al. Structural analysis of papain-like NlpC/P60 superfamily enzymes with a circularly permuted topology reveals potential lipid binding sites. PLoS ONE 6, e22013 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bylebyl, G. R., Belichenko, I. & Johnson, E. S. The SUMO isopeptidase Ulp2 prevents accumulation of SUMO chains in yeast. J. Biol. Chem. 278, 44113–44120 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Elmore, Z. C. et al. SUMO-dependent substrate targeting of the SUMO protease Ulp1. BMC Biol. 9, 74 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. Kolli, N. et al. Distribution and paralogue specificity of mammalian deSUMOylating enzymes. Biochem. J. 430, 335–344 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Di Bacco, A. et al. The SUMO-specific protease SENP5 is required for cell division. Mol. Cell. Biol. 26, 4489–4498 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hattersley, N., Shen, L., Jaffray, E. G. & Hay, R. T. The SUMO protease SENP6 is a direct regulator of PML nuclear bodies. Mol. Biol. Cell 22, 78–90 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhu, S. et al. Protection from isopeptidase-mediated deconjugation regulates paralog-selective sumoylation of RanGAP1. Mol. Cell 33, 570–580 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xu, Z. & Au, S. W. Mapping residues of SUMO precursors essential in differential maturation by SUMO-specific protease, SENP1. Biochem. J. 386, 325–330 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bawa-Khalfe, T., Cheng, J., Wang, Z. & Yeh, E. T. Induction of the SUMO-specific protease 1 transcription by the androgen receptor in prostate cancer cells. J. Biol. Chem. 282, 37341–37349 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Xu, Y. et al. Induction of SENP1 in endothelial cells contributes to hypoxia-driven VEGF expression and angiogenesis. J. Biol. Chem. 285, 36682–36688 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cheng, J., Kang, X., Zhang, S. & Yeh, E. T. SUMO-specific protease 1 is essential for stabilization of HIF1α during hypoxia. Cell 131, 584–595 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lee, M. H., Mabb, A. M., Gill, G. B., Yeh, E. T. & Miyamoto, S. NF-κB induction of the SUMO protease SENP2: a negative feedback loop to attenuate cell survival response to genotoxic stress. Mol. Cell 43, 180–191 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Kuo, M. L., den Besten, W., Thomas, M. C. & Sherr, C. J. Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3 protease Senp3. Cell Cycle 7, 3378–3387 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Huang, C. et al. SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation. EMBO J. 28, 2748–2762 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yan, S. et al. Redox regulation of the stability of the SUMO protease SENP3 via interactions with CHIP and Hsp90. EMBO J. 29, 3773–3786 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Baldwin, M. L., Julius, J. A., Tang, X., Wang, Y. & Bachant, J. The yeast SUMO isopeptidase Smt4/Ulp2 and the polo kinase Cdc5 act in an opposing fashion to regulate sumoylation in mitosis and cohesion at centromeres. Cell Cycle 8, 3406–3419 (2009).

    Article  CAS  PubMed  Google Scholar 

  61. Golebiowski, F. et al. System-wide changes to SUMO modifications in response to heat shock. Sci Signal 2, ra24 (2009).

    Article  PubMed  CAS  Google Scholar 

  62. Pinto, M. P. et al. Heat shock induces a massive but differential inactivation of SUMO-specific proteases. Biochim. Biophys. Acta 1823, 1958–1966 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Truong, K., Lee, T. D. & Chen, Y. Small ubiquitin-like modifier (SUMO) modification of E1 Cys domain inhibits E1 Cys domain enzymatic activity. J. Biol. Chem. 287, 15154–15163 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Xu, Z. et al. Molecular basis of the redox regulation of SUMO proteases: a protective mechanism of intermolecular disulfide linkage against irreversible sulfhydryl oxidation. FASEB J. 22, 127–137 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Kang, X. et al. SUMO-specific protease 2 is essential for suppression of polycomb group protein-mediated gene silencing during embryonic development. Mol. Cell 38, 191–201 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hwang, E. J. et al. SUMOylation of RORα potentiates transcriptional activation function. Biochem. Biophys. Res. Commun. 378, 513–517 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Alm-Kristiansen, A. H., Norman, I. L., Matre, V. & Gabrielsen, O. S. SUMO modification regulates the transcriptional activity of FLASH. Biochem. Biophys. Res. Commun. 387, 494–499 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Witty, J., Aguilar-Martinez, E. & Sharrocks, A. D. SENP1 participates in the dynamic regulation of Elk-1 SUMOylation. Biochem. J. 428, 247–254 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Lindberg, M. J., Popko-Scibor, A. E., Hansson, M. L. & Wallberg, A. E. SUMO modification regulates the transcriptional activity of MAML1. FASEB J. 24, 2396–2404 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Murata, T. et al. Transcriptional repression by sumoylation of Epstein–Barr virus BZLF1 protein correlates with association of histone deacetylase. J. Biol. Chem. 285, 23925–23935 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kaikkonen, S., Makkonen, H., Rytinki, M. & Palvimo, J. J. SUMOylation can regulate the activity of ETS-like transcription factor 4. Biochim. Biophys. Acta 1799, 555–560 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Choi, H. K. et al. Reversible SUMOylation of TBL1–TBLR1 regulates β-catenin-mediated Wnt signaling. Mol. Cell 43, 203–216 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Shimshon, L. et al. SUMOylation of Blimp-1 promotes its proteasomal degradation. FEBS Lett. 585, 2405–2409 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Cong, L., Pakala, S. B., Ohshiro, K., Li, D. Q. & Kumar, R. SUMOylation and SUMO-interacting motif (SIM) of metastasis tumor antigen 1 (MTA1) synergistically regulate its transcriptional repressor function. J. Biol. Chem. 286, 43793–43808 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chang, T. H., Xu, S., Tailor, P., Kanno, T. & Ozato, K. The small ubiquitin-like modifier-deconjugating enzyme sentrin-specific peptidase 1 switches IFN regulatory factor 8 from a repressor to an activator during macrophage activation. J. Immunol. 189, 3548–3556 (2012)

    Article  CAS  PubMed  Google Scholar 

  76. Lyst, M. J. & Stancheva, I. A role for SUMO modification in transcriptional repression and activation. Biochem. Soc. Trans. 35, 1389–1392 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yang, S. H. & Sharrocks, A. D. SUMO promotes HDAC-mediated transcriptional repression. Mol. Cell 13, 611–617 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Li, X. et al. SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis. Cell Death Differ. 15, 739–750 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Stelter, P. & Ulrich, H. D. Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425, 188–191 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Leisner, C. et al. Regulation of mitotic spindle asymmetry by SUMO and the spindle-assembly checkpoint in yeast. Curr. Biol. 18, 1249–1255 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schwartz, D. C., Felberbaum, R. & Hochstrasser, M. The Ulp2 SUMO protease is required for cell division following termination of the DNA damage checkpoint. Mol. Cell. Biol. 27, 6948–6961 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lee, M. T., Bakir, A. A., Nguyen, K. N. & Bachant, J. The SUMO isopeptidase Ulp2p is required to prevent recombination-induced chromosome segregation lethality following DNA replication stress. PLoS Genet. 7, e1001355 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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).

    Article  CAS  PubMed  Google Scholar 

  85. Bergink, S. & Jentsch, S. Principles of ubiquitin and SUMO modifications in DNA repair. Nature 458, 461–467 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Mukhopadhyay, D., Arnaoutov, A. & Dasso, M. The SUMO protease SENP6 is essential for inner kinetochore assembly. J. Cell Biol. 188, 681–692 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Panse, V. G. et al. Formation and nuclear export of preribosomes are functionally linked to the small-ubiquitin-related modifier pathway. Traffic 7, 1311–1321 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Haindl, M., Harasim, T., Eick, D. & Muller, S. The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing. EMBO Rep. 9, 273–279 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yun, C. et al. Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases. J. Cell Biol. 183, 589–595 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Finkbeiner, E., Haindl, M. & Muller, S. The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex. EMBO J. 30, 1067–1078 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Savkur, R. S. & Olson, M. O. Preferential cleavage in pre-ribosomal RNA byprotein B23 endoribonuclease. Nucleic Acids Res. 26, 4508–4515 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Grisendi, S., Mecucci, C., Falini, B. & Pandolfi, P. P. Nucleophosmin and cancer. Nature Rev. Cancer 6, 493–505 (2006).

    Article  CAS  Google Scholar 

  93. Nissan, T. A. et al. A pre-ribosome with a tadpole-like structure functions in ATP-dependent maturation of 60S subunits. Mol. Cell 15, 295–301 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Krogan, N. J. et al. High-definition macromolecular composition of yeast RNA-processing complexes. Mol. Cell 13, 225–239 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Harder, Z., Zunino, R. & McBride, H. Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr. Biol. 14, 340–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Zunino, R., Schauss, A., Rippstein, P., Andrade-Navarro, M. & McBride, H. M. The SUMO protease SENP5 is required to maintain mitochondrial morphology and function. J. Cell Sci. 120, 1178–1188 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Zunino, R., Braschi, E., Xu, L. & McBride, H. M. Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis. J. Biol. Chem. 284, 17783–17795 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Prudden, J. et al. SUMO-targeted ubiquitin ligases in genome stability. EMBO J. 26, 4089–4101 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sun, H., Leverson, J. D. & Hunter, T. Conserved function of RNF4 family proteins in eukaryotes: targeting a ubiquitin ligase to SUMOylated proteins. EMBO J. 26, 4102–4112 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Xie, Y. et al. The yeast Hex3•Slx8 heterodimer is a ubiquitin ligase stimulated by substrate sumoylation. J. Biol. Chem. 282, 34176–34184 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Uzunova, K. et al. Ubiquitin-dependent proteolytic control of SUMO conjugates. J. Biol. Chem. 282, 34167–34175 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Plechanovova, A. et al. Mechanism of ubiquitylation by dimeric RING ligase RNF4. Nature Struct. Mol. Biol. 18, 1052–1059 (2011).

    Article  CAS  Google Scholar 

  103. Plechanovova, A., Jaffray, E. G., Tatham, M. H., Naismith, J. H. & Hay, R. T. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489, 115–120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Abed, M. et al. Degringolade, a SUMO-targeted ubiquitin ligase, inhibits Hairy/Groucho-mediated repression. EMBO J. 30, 1289–1301 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yin, Y. et al. SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage. Genes Dev. 26, 1196–1208 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Galanty, Y., Belotserkovskaya, R., Coates, J. & Jackson, S. P. RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. Genes Dev. 26, 1179–1195 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dou, H., Huang, C., Singh, M., Carpenter, P. B. & Yeh, E. T. Regulation of DNA repair through deSUMOylation and SUMOylation of replication protein A complex. Mol. Cell 39, 333–345 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wang, Z., Jones, G. M. & Prelich, G. Genetic analysis connects SLX5 and SLX8 to the SUMO pathway in Saccharomyces cerevisiae. Genetics 172, 1499–1509 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mullen, J. R., Das, M. & Brill, S. J. Genetic evidence that polysumoylation bypasses the need for a SUMO-targeted Ub ligase. Genetics 187, 73–87 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wang, Z. & Prelich, G. Quality control of a transcriptional regulator by SUMO-targeted degradation. Mol. Cell. Biol. 29, 1694–1706 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Zhou, W., Ryan, J. J. & Zhou, H. Global analyses of sumoylated proteins in Saccharomyces cerevisiae. Induction of protein sumoylation by cellular stresses. J. Biol. Chem. 279, 32262–32268 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Felberbaum, R., Wilson, N. R., Cheng, D., Peng, J. & Hochstrasser, M. Desumoylation of the endoplasmic reticulum membrane VAP family protein Scs2 by Ulp1 and SUMO regulation of the inositol synthesis pathway. Mol. Cell. Biol. 32, 64–75 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sydorskyy, Y. et al. A novel mechanism for SUMO system control: regulated Ulp1 nucleolar sequestration. Mol. Cell. Biol. 30, 4452–4462 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mullen, J. R. & Brill, S. J. Activation of the Slx5–Slx8 ubiquitin ligase by poly-small ubiquitin-like modifier conjugates. J. Biol. Chem. 283, 19912–19921 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mullen, J. R., Chen, C. F. & Brill, S. J. Wss1 is a SUMO-dependent isopeptidase that interacts genetically with the Slx5–Slx8 SUMO-targeted ubiquitin ligase. Mol. Cell. Biol. 30, 3737–3748 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Namanja, A. T. et al. Insights into high affinity small ubiquitin-like modifier (SUMO) recognition by SUMO-interacting motifs (SIMs) revealed by a combination of NMR and peptide array analysis. J. Biol. Chem. 287, 3231–3240 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Song, J., Zhang, Z., Hu, W. & Chen, Y. Small ubiquitin-like modifier (SUMO) recognition of a SUMO binding motif: a reversal of the bound orientation. J. Biol. Chem. 280, 40122–40129 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Hecker, C. M., Rabiller, M., Haglund, K., Bayer, P. & Dikic, I. Specification of SUMO1- and SUMO2-interacting motifs. J. Biol. Chem. 281, 16117–16127 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Rendtlew Danielsen, J. et al. DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO-binding zinc finger. J. Cell Biol. 197, 179–187 (2012).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank C. Schlieker and J. Gillies for their helpful comments on the manuscript. They also acknowledge support from the US National Institutes of Health (NIH grants GM046904 and GM053756 to M.H.), an NIH National Research Service Award (NRSA) postdoctoral fellowship (F32 GM097794 to C.M.H.) and a National Science Foundation (NSF) predoctoral fellowship (to N.R.W.).

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  1. Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, 06520, Connecticut, USA

    Christopher M. Hickey, Nicole R. Wilson & Mark Hochstrasser

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  1. Christopher M. Hickey
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Correspondence to Mark Hochstrasser.

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Glossary

Scissile bond

The bond within a substrate that is subject to enzymatic cleavage.

Nuclear pore complex

(NPC). Large multiprotein complex that forms a channel in the nuclear envelope of an eukaryotic cell. The NPC joins the inner and outer nuclear membranes and allows transport of proteins to and from the nucleus.

Septin

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

Response elements

Short DNA sequences within the promoter region of a gene that binds specific DNA-binding transcription factors, thus regulating the transcription of the (typically adjacent) gene.

Ubiquitin–proteasome system

(UPS). A system of selective, ATP-dependent protein degradation, in which ubiquitin-conjugated target proteins are degraded by the 26S proteasome.

Histone deacetylases

(HDACs). Enzymes that remove the acetyl groups of core histones. Their activity has an important function in transcriptional regulation and cell cycle progression via alterations in chromatin structure.

Polycomb-related repressors

A family of proteins that can remodel chromatin and silence genes. This protein family was first discovered in Drosophila melanogaster.

Centromere

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

Homologous recombination

A DNA recombination pathway that includes the repair of double-strand DNA breaks. This pathway uses a homologous double-stranded DNA molecule as a template for the repair of the broken DNA.

Mitochondrial fission

Mitochondrial membrane constriction and scission that promote fragmentation of the mitochondrial network. The process is highly regulated and, together with the opposing process of mitochondrial fusion (joining), is responsible for the dynamics observed for the mitochondrial network.

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Hickey, C., Wilson, N. & Hochstrasser, M. Function and regulation of SUMO proteases. Nat Rev Mol Cell Biol 13, 755–766 (2012). https://doi.org/10.1038/nrm3478

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