Advertisement

Roles for SUMO Modification during Senescence

  • Artemisia M. Andreou
  • Nektarios Tavernarakis
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 694)

Abstract

SUMOylation is a reversible post-translational modification, where a small peptide (SUMO) is covalently attached to a target protein and changes its activity, subcellular localization and/or interaction with other macromolecules. SUMOylation substrates are numerous and diverse and modification by SUMO is involved in many biological functions, including the response to stress. The SUMO pathway has recently been implicated in the process of cellular senescence, the irreversible loss of cell replication potential that occurs during aging in vivo and in vitro. SUMO peptides, a SUMO E3 ligase and a SUMO-specific peptidase can induce or hinder the onset of senescence, thus supporting an association of SUMOylation with cell growth arrest and organismal aging. Preliminary results on comparative analysis of proteomics and mRNA levels between young and old human and murine tissues show elevated levels of global protein SUMOylation and a decrease in components of the SUMOylation process with age. Further connections between the SUMO pathway and the aging process remain to be elucidated.

Keywords

Cellular Senescence Senescent Cell Replicative Senescence Protein SUMOylation Sumo Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bayer P, Arndt A, Metzger S et al. Structure determination of the small ubiquitin-related modifier SUMO-1. J Mol Biol 1998; 280(2):275–286.CrossRefPubMedGoogle Scholar
  2. 2.
    Jin C, Shiyanova T, Shen Z et al. Heteronuclear nuclear magnetic resonance assignments, structure and dynamics of SUMO-1, a human ubiquitin-like protein. Int J Biol Macromol 2001; 28(3):227–234.CrossRefPubMedGoogle Scholar
  3. 3.
    Johnson ES. Protein modification by SUMO. Annu Rev Biochem 2004; 73:355–382.CrossRefPubMedGoogle Scholar
  4. 4.
    Bohren KM, Nadkarni V, Song JH et al. A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. J Biol Chem 2004; 279(26):27233–27238.CrossRefPubMedGoogle Scholar
  5. 5.
    Saitoh H, Hinchey J. Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem 2000; 275(9):6252–6258.CrossRefPubMedGoogle Scholar
  6. 6.
    Hay RT. SUMO: a history of modification. Mol Cell 2005; 18(1):1–12.CrossRefPubMedGoogle Scholar
  7. 7.
    Gill G. Something about SUMO inhibits transcription. Curr Opin Genet Dev 2005; 15(5):536–541.CrossRefPubMedGoogle Scholar
  8. 8.
    Sampson DA, Wang M, Matunis MJ. The small ubiquitin-like modifier-1 (SUMO-1) consensus sequence mediates Ubc9 binding and is essential for SUMO-1 modification. J Biol Chem 2001; 276(24):21664–21669.CrossRefPubMedGoogle Scholar
  9. 9.
    Melchior F, Schergaut M, Pichler A. SUMO: ligases, isopeptidases and nuclear pores. Trends Biochem Sci 2003; 28(11):612–618.CrossRefPubMedGoogle Scholar
  10. 10.
    Minty A, Dumont X, Kaghad M et al. Covalent modification of p73alpha by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif. J Biol Chem 2000; 275(46):36316–36323.CrossRefPubMedGoogle Scholar
  11. 11.
    Rodriguez MS, Dargemont C, Hay RT. SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J Biol Chem 2001; 276(16):12654–12659.CrossRefPubMedGoogle Scholar
  12. 12.
    Song J, Durrin LK, Wilkinson TA et al. Identification of a SUMO-binding motif that recognizes SUMO-modified proteins. Proc Natl Acad Sci USA 2004; 101(40):14373–14378.CrossRefPubMedGoogle Scholar
  13. 13.
    Yang SH, Galanis A, Witty J et al. An extended consensus motif enhances the specificity of substrate modification by SUMO. EMBO J 2006; 25(21):5083–5093.CrossRefPubMedGoogle Scholar
  14. 14.
    Desterro JM, Rodriguez MS, Hay RT. SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell 1998; 2(2):233–239.CrossRefPubMedGoogle Scholar
  15. 15.
    Hoege C, Pfander B, Moldovan GL et al. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 2002; 419(6903):135–141.CrossRefPubMedGoogle Scholar
  16. 16.
    Hietakangas V, Anckar J, Blomster HA et al. PDSM, a motif for phosphorylation-dependent SUMO modification. Proc Natl Acad Sci USA 2006; 103(1):45–50.CrossRefPubMedGoogle Scholar
  17. 17.
    Bossis G, Malnou CE, Farras R et al. Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol 2005; 25(16):6964–6979.CrossRefPubMedGoogle Scholar
  18. 18.
    Lin JY, Ohshima T, Shimotohno K. Association of Ubc9, an E2 ligase for SUMO conjugation, with p53 is regulated by phosphorylation of p53. FEBS Lett 2004; 573(1–3):15–18.CrossRefPubMedGoogle Scholar
  19. 19.
    Muller S, Berger M, Lehembre F et al. c-Jun and p53 activity is modulated by SUMO-1 modification. J Biol Chem 2000; 275(18):13321–13329.CrossRefPubMedGoogle Scholar
  20. 20.
    Girdwood D, Bumpass D, Vaughan OA et al. P300 transcriptional repression is mediated by SUMO modification. Mol Cell 2003; 11(4):1043–1054.CrossRefPubMedGoogle Scholar
  21. 21.
    Yang SH, Sharrocks AD. SUMO promotes HDAC-mediated transcriptional repression. Mol Cell 2004; 13(4):611–617.CrossRefPubMedGoogle Scholar
  22. 22.
    Stankovic-Valentin N, Deltour S, Seeler J et al. An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. Mol Cell Biol 2007; 27(7):2661–2675.CrossRefPubMedGoogle Scholar
  23. 23.
    Shiio Y, Eisenman RN. Histone sumoylation is associated with transcriptional repression. Proc Natl Acad Sci USA 2003; 100(23):13225–13230.CrossRefPubMedGoogle Scholar
  24. 24.
    Li SJ, Hochstrasser M. A new protease required for cell-cycle progression in yeast. Nature 1999; 398(6724):246–251.CrossRefPubMedGoogle Scholar
  25. 25.
    Li SJ, Hochstrasser M. The yeast ULP2 (SMT4) gene encodes a novel protease specific for the ubiquitin-like Smt3 protein. Mol Cell Biol 2000; 20(7):2367–2377.CrossRefPubMedGoogle Scholar
  26. 26.
    Azuma Y, Tan SH, Cavenagh MM et al. Expression and regulation of the mammalian SUMO-1 E1 enzyme. FASEB J 2001; 15(10):1825–1827.PubMedGoogle Scholar
  27. 27.
    Bailey D, O’Hare P. Characterization of the localization and proteolytic activity of the SUMO-specific protease, SENP1. J Biol Chem 2004; 279(1):692–703.CrossRefPubMedGoogle Scholar
  28. 28.
    Mukhopadhyay D, Dasso M. Modification in reverse: the SUMO proteases. Trends Biochem Sci 2007; 32(6):286–295.CrossRefPubMedGoogle Scholar
  29. 29.
    Bailey D, O’Hare P. Herpes simplex virus 1 ICP0 colocalizes with a SUMO-specific protease. J Gen Virol 2002; 83(Pt 12):2951–2964.PubMedGoogle Scholar
  30. 30.
    Gong L, Millas S, Maul GG et al. Differential regulation of sentrinized proteins by a novel sentrin-specific protease. J Biol Chem 2000; 275(5):3355–3359.CrossRefPubMedGoogle Scholar
  31. 31.
    Hang J, Dasso M. Association of the human SUMO-1 protease SENP2 with the nuclear pore. J Biol Chem 2002; 277(22):19961–19966.CrossRefPubMedGoogle Scholar
  32. 32.
    Li SJ, Hochstrasser M. The Ulp1 SUMO isopeptidase: distinct domains required for viability, nuclear envelope localization and substrate specificity. J Cell Biol 2003; 160(7):1069–1081.CrossRefPubMedGoogle Scholar
  33. 33.
    Gong L, Yeh ET. Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J Biol Chem 2006; 281(23):15869–15877.CrossRefPubMedGoogle Scholar
  34. 34.
    Kim KI, Baek SH, Jeon YJ et al. A new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs. J Biol Chem 2000; 275(19):14102–14106.CrossRefPubMedGoogle Scholar
  35. 35.
    Mukhopadhyay D, Ayaydin F, Kolli N et al. SUSP1 antagonizes formation of highly SUMO2/3-conjugated species. J Cell Biol 2006; 174(7):939–949.CrossRefPubMedGoogle Scholar
  36. 36.
    Ayaydin F, Dasso M. Distinct in vivo dynamics of vertebrate SUMO paralogues. Mol Biol Cell 2004; 15(12):5208–5218.CrossRefPubMedGoogle Scholar
  37. 37.
    Geiss-Friedlander R, Melchior F. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 2007; 8(12):947–956.CrossRefPubMedGoogle Scholar
  38. 38.
    Papouli E, Chen S, Davies AA et al. Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p. Mol Cell 2005; 19(1):123–133.CrossRefPubMedGoogle Scholar
  39. 39.
    Pfander B, Moldovan GL, Sacher M et al. SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase. Nature 2005; 436(7049):428–433.PubMedGoogle Scholar
  40. 40.
    Lin X, Sun B, Liang M et al. Opposed regulation of corepressor CtBP by SUMOylation and PDZ binding. Mol Cell 2003; 11(5):1389–1396.CrossRefPubMedGoogle Scholar
  41. 41.
    Baba D, Maita N, Jee JG et al. Crystal structure of thymine DNA glycosylase conjugated to SUMO-1. Nature 2005; 435(7044):979–982.CrossRefPubMedGoogle Scholar
  42. 42.
    Hardeland U, Steinacher R, Jiricny J et al. Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover. EMBO J 2002; 21(6):1456–1464.CrossRefPubMedGoogle Scholar
  43. 43.
    Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961; 25:585–621.CrossRefGoogle Scholar
  44. 44.
    Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 2001; 11(11):S27–31.CrossRefPubMedGoogle Scholar
  45. 45.
    Green DR, Evan GI. A matter of life and death. Cancer Cell 2002; 1(1):19–30.CrossRefPubMedGoogle Scholar
  46. 46.
    Jeyapalan JC, Sedivy JM. Cellular senescence and organismal aging. Mech Ageing Dev 2008; 129(7–8):467–474.CrossRefPubMedGoogle Scholar
  47. 47.
    Keyes WM, Wu Y, Vogel H et al. p63 deficiency activates a program of cellular senescence and leads to accelerated aging. Genes Dev 2005; 19(17):1986–1999.CrossRefPubMedGoogle Scholar
  48. 48.
    Chen JH, Hales CN, Ozanne SE. DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res 2007; 35(22):7417–7428.CrossRefPubMedGoogle Scholar
  49. 49.
    Dimri GP. What has senescence got to do with cancer? Cancer Cell 2005; 7(6):505–512.CrossRefPubMedGoogle Scholar
  50. 50.
    Dimri GP, Lee X, Basile G et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92(20):9363–9367.CrossRefPubMedGoogle Scholar
  51. 51.
    Goldstein S. Replicative senescence: the human fibroblast comes of age. Science 1990; 249(4973):1129–1133.CrossRefPubMedGoogle Scholar
  52. 52.
    Shay JW, Wright WE. Telomeres and telomerase: implications for cancer and aging. Radiat Res 2001; 155(1 Pt 2):188–193.CrossRefPubMedGoogle Scholar
  53. 53.
    Stewart SA, Weinberg RA. Telomerase and human tumorigenesis. Semin Cancer Biol 2000; 10(6):399–406.CrossRefPubMedGoogle Scholar
  54. 54.
    Bodnar AG, Ouellette M, Frolkis M et al. Extension of life-span by introduction of telomerase into normal human cells. Science 1998; 279(5349):349–352.CrossRefPubMedGoogle Scholar
  55. 55.
    Wright WE, Shay JW. Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nat Med 2000; 6(8):849–851.CrossRefPubMedGoogle Scholar
  56. 56.
    Chang S, Multani AS, Cabrera NG et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat Genet 2004; 36(8):877–882.CrossRefPubMedGoogle Scholar
  57. 57.
    Choudhury AR, Ju Z, Djojosubroto MW et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 2007; 39(1):99–105.CrossRefPubMedGoogle Scholar
  58. 58.
    Serrano M, Blasco MA. Putting the stress on senescence. Curr Opin Cell Biol 2001; 13(6):748–753.CrossRefPubMedGoogle Scholar
  59. 59.
    Ohtani N, Mann DJ, Hara E. Cellular senescence: its role in tumor suppression and aging. Cancer Sci 2009; 100(5):792–797.CrossRefPubMedGoogle Scholar
  60. 60.
    Hardy K, Mansfield L, Mackay A et al. Transcriptional networks and cellular senescence in human mammary fibroblasts. Mol Biol Cell 2005; 16(2):943–953.CrossRefPubMedGoogle Scholar
  61. 61.
    Johung K, Goodwin EC, DiMaio D. Human papillomavirus E7 repression in cervical carcinoma cells initiates a transcriptional cascade driven by the retinoblastoma family, resulting in senescence. J Virol 2007; 81(5):2102–2116.CrossRefPubMedGoogle Scholar
  62. 62.
    Campisi J. Senescent cells, tumor supression and organismal aging: good citizens, bad neighbors. Cell 2005; 120:513–522.CrossRefPubMedGoogle Scholar
  63. 63.
    Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 2004; 4(8):592–603.CrossRefPubMedGoogle Scholar
  64. 64.
    Ben-Porath IaW RA. When cells get stressed: an integrative view of cellular senescence. J Clin Invest 2004; 113:8–13.Google Scholar
  65. 65.
    Hickman ES, Moroni MC, Helin K. The role of p53 and pRB in apoptosis and cancer. Curr Opin Genet Dev 2002; 12:60–66.CrossRefPubMedGoogle Scholar
  66. 66.
    Comerford KM, Leonard MO, Karhausen J et al. Small ubiquitin-related modifier-1 modification mediates resolution of CREB-dependent responses to hypoxia. Proc Natl Acad Sci USA 2003; 100(3):986–991.CrossRefPubMedGoogle Scholar
  67. 67.
    Li T, Santockyte R, Shen RF et al. Expression of SUMO-2/3 induced senescence through p53-and pRB-mediated pathways. J Biol Chem 2006; 281:36221–36227.CrossRefPubMedGoogle Scholar
  68. 68.
    Bischof O, Dejean A. SUMO is growing senescent. Cell Cycle 2007; 6:677–681.PubMedGoogle Scholar
  69. 69.
    Akar CA, Feinstein DL. Modulation of inducible nitric oxide synthase expression by sumoylation. J Neuroinflammation 2009; 6:12.CrossRefPubMedGoogle Scholar
  70. 70.
    Li T, Evdokimov E, Shen RF et al. Sumoylation of heterogeneous nuclear ribonucleoproteins, zinc finger proteins and nuclear pore complex proteins: a proteomic analysis. Proc Natl Acad Sci USA 2004; 101(23):8551–8556.CrossRefPubMedGoogle Scholar
  71. 71.
    Gostissa M, Hengstermann A, Fogal V et al. Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J 1999; 18:6462–6471.CrossRefPubMedGoogle Scholar
  72. 72.
    Ledl A, Schmidt D, Muller S. Viral oncoproteins E1A and E7 and cellular LxCxE proteins repress SUMO modification of the retinoblastoma tumor supressor. Oncogene 2005; 24:3810–3818.CrossRefPubMedGoogle Scholar
  73. 73.
    Rodriguez M, Desterro JM, Lain S et al. SUMO-1 modification activates the transcriptional response of p53. EMBO J 1999; 18:6455–6461.CrossRefPubMedGoogle Scholar
  74. 74.
    Bischof O, Schwamborn K, Martin N et al. The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis. Mol Cell 2006; 22(6):783–794.CrossRefPubMedGoogle Scholar
  75. 75.
    Sugrue MM, Shin DY, Lee SW et al. Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53. Proc Natl Acad Sci USA 1997; 97:9648–9653.CrossRefGoogle Scholar
  76. 76.
    Schmidt DaM S. PIAS/SUMO: new partners in transcriptional regulation. Cell Mol Life Sci 2003; 60:2561–2574.CrossRefGoogle Scholar
  77. 77.
    Uchimura Y, Ichimura T, Uwada J et al. Involvement of SUMO modification in MBD1-and MCAF1-mediated heterochromatin formation. J Biol Chem 2006; 281:23180–23190.CrossRefPubMedGoogle Scholar
  78. 78.
    Nathan D, Ingvarsdottir K, Sterner DE et al. Histone sumoylation is a negative regulator in Saccharomyces serevisiae and shown dynamic interplay with positive-acting histone modifications. Genes Dev 2006; 20:966–976.CrossRefPubMedGoogle Scholar
  79. 79.
    Yates KE, Korbel GA, Shtutman M et al. Repression of the SUMO-specific protease Senp1 induces p53-dependent premature senescence in normal human fibroblasts. Aging Cell 2008; 7(5):609–621.CrossRefPubMedGoogle Scholar
  80. 80.
    de Lange T. Shelterin: The protein complex that shapes and safeguards human telomeres. Genes Dev 2005; 19:2100–2110.CrossRefPubMedGoogle Scholar
  81. 81.
    Stewart SA, Weinberg RA. Telomeres: Cancer to human aging. Annu Rev Cell Dev Biol 2006; 22:531–557.CrossRefPubMedGoogle Scholar
  82. 82.
    Tanaka K, Nishide J, Okazaki 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 1999; 19:8660–8672.PubMedGoogle Scholar
  83. 83.
    Xhemalce B, Seeler JS, Thon G et al. Role of the fission yeast SUMO E3 ligase Pli1p in centromere and telomere maintenance. EMBO J 2004; 23:3844–3853.CrossRefPubMedGoogle Scholar
  84. 84.
    Zhang L, Li F, Dimayuga E et al. Effects of aging and dietary restriction on ubiquitination, sumoylation and the proteasome in the spleen. FEBS Lett 2007; 581:5543–5547.CrossRefPubMedGoogle Scholar
  85. 85.
    Wei F, Scholer HR, Atchison ML. Sumoylation od Oct4 enhances its stability, DNA binding and transactivation. J Biol Chem 2007; 282:21551–21560.CrossRefPubMedGoogle Scholar
  86. 86.
    de Cristofaro T, Mascia A, Pappalardo A et al. Pax8 protein stability is controlled by sumoylation. J Mol Endocrinol 2009; 42:35–46.CrossRefPubMedGoogle Scholar
  87. 87.
    Yurchenko V, Xue Z, Gama V et al. Ku70 is stabilized ny increased cellular SUMO. Biochem Biophys Res Commun 2008; 366:263–268.CrossRefPubMedGoogle Scholar
  88. 88.
    Benanti J, Williams DK, Robinson KL et al. Induction of extracellular matrix-remodelling genes by the senescence-associated protein APA-1. Mol Cell Biol 2002; 22:7385–7397.CrossRefPubMedGoogle Scholar
  89. 89.
    Cheng J, Kang X, Zhang S et al. SUMO-specific protease 1 is essential for stabilization of hypoxia-inducible factor-1a during hypoxia. Cell 2007; 131:584–595.CrossRefPubMedGoogle Scholar
  90. 90.
    Wang YT, Chuang JY, Shen MR et al. Sumoylation of specificity protein 1 augments its degradation by changing the localization and increasing the specificity protein 1 proteolytic process. J Mol Biol 2008; 380:869–885.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Institute of Molecular Biology and Biotechnology (IMBB)Foundation for Research and Technology Hellas (FORTH)CreteGreece

Personalised recommendations