Abstract
Cellular signaling pathways largely depend on the plasticity of multiprotein complexes. A central mechanism that assures the coordinated assembly and disassembly of protein complexes is the reversible post-translational modification of the individual components for example by phosphorylation, acetylation, or ubiquitylation. Accumulating evidence indicates that the small ubiquitin-related modifier (SUMO) system is another master organizer of protein complexes. Here, we will focus on the role of SUMO in the regulation of nuclear protein complexes that are involved in chromatin remodeling, double-strand break repair, and ribosome biogenesis. On the basis of these selected pathways, we will summarize current ideas of SUMO signaling, including the concept of group modification and the intersection of the ubiquitin and SUMO pathways.
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References
Bassler J, Kallas M, Pertschy B, Ulbrich C, Thoms M, Hurt E (2010) The AAA-ATPase Rea1 drives removal of biogenesis factors during multiple stages of 60S ribosome assembly. Mol Cell 38(5):712–721. doi:10.1016/j.molcel.2010.05.024
Begitt A, Droescher M, Knobeloch KP, Vinkemeier U (2011) SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNgamma. Blood 118(4):1002–1007. doi:10.1182/blood-2011-04-347930
Bekker-Jensen S, Mailand N (2010) Assembly and function of DNA double-strand break repair foci in mammalian cells. DNA Repair 9(12):1219–1228. doi:10.1016/j.dnarep.2010.09.010
Bergink S, Ammon T, Kern M, Schermelleh L, Leonhardt H, Jentsch S (2013) Role of Cdc48/p97 as a SUMO-targeted segregase curbing Rad51-Rad52 interaction. Nat Cell Biol 15(5):526–532. doi:10.1038/ncb2729
Bergink S, Jentsch S (2009) Principles of ubiquitin and SUMO modifications in DNA repair. Nature 458(7237):461–467. doi:10.1038/nature07963
Bernardi R, Pandolfi PP (2007) Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol 8(12):1006–1016. doi:10.1038/nrm2277
Bies J, Markus J, Wolff L (2002) 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(11):8999–9009. doi:10.1074/jbc.M110453200
Bossis G, Malnou CE, Farras R, Andermarcher E, Hipskind R, Rodriguez M, Schmidt D, Muller S, Jariel-Encontre I, Piechaczyk M (2005) Downregulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol 25(16):6964–6979. doi:10.1128/MCB.25.16.6964-6979.2005
Castle CD, Cassimere EK, Denicourt C (2012) LAS1L interacts with the mammalian Rix1 complex to regulate ribosome biogenesis. Mol Biol Cell 23(4):716–728. doi:10.1091/mbc.E11-06-0530
Castle CD, Cassimere EK, Lee J, Denicourt C (2010) Las1L is a nucleolar protein required for cell proliferation and ribosome biogenesis. Mol Cell Biol 30(18):4404–4414. doi:10.1128/MCB.00358-10
Chang CC, Naik MT, Huang YS, Jeng JC, Liao PH, Kuo HY, Ho CC, Hsieh YL, Lin CH, Huang NJ, Naik NM, Kung CC, Lin SY, Chen RH, Chang KS, Huang TH, Shih HM (2011) Structural and functional roles of Daxx SIM phosphorylation in SUMO paralog-selective binding and apoptosis modulation. Mol Cell 42(1):62–74. doi:10.1016/j.molcel.2011.02.022
Chapman JR, Taylor MR, Boulton SJ (2012) Playing the end game: DNA double-strand break repair pathway choice. Mol Cell 47(4):497–510. doi:10.1016/j.molcel.2012.07.029
Chupreta S, Holmstrom S, Subramanian L, Iniguez-Lluhi JA (2005) A small conserved surface in SUMO is the critical structural determinant of its transcriptional inhibitory properties. Mol Cell Biol 25(10):4272–4282. doi:10.1128/MCB.25.10.4272-4282.2005
David G, Neptune MA, DePinho RA (2002) SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities. J Biol Chem 277(26):23658–23663. doi:10.1074/jbc.M203690200
Dikic I, Wakatsuki S, Walters KJ (2009) Ubiquitin-binding domains—from structures to functions. Nat Rev Mol Cell Biol 10(10):659–671. doi:10.1038/nrm2767
Erker Y, Neyret-Kahn H, Seeler JS, Dejean A, Atfi A, Levy L (2013) Arkadia, a novel SUMO-targeted ubiquitin ligase involved in PML degradation. Mol Cell Biol 33(11):2163–2177. doi:10.1128/MCB.01019-12
Finkbeiner E, Haindl M, Muller S (2011a) The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex. EMBO J 30(6):1067–1078. doi:10.1038/emboj.2011.33
Finkbeiner E, Haindl M, Raman N, Muller S (2011b) SUMO routes ribosome maturation. Nucleus 2(6):527–532. doi:10.4161/nucl.2.6.17604
Galanty Y, Belotserkovskaya R, Coates J, Jackson SP (2012) RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. Genes Dev 26(11):1179–1195. doi:10.1101/gad.188284.112
Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM, Jackson SP (2009) Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 462(7275):935–939. doi:10.1038/nature08657
Gareau JR, Lima CD (2010) The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 11(12):861–871. doi:10.1038/nrm3011
Gostissa M, Hengstermann A, Fogal V, Sandy P, Schwarz SE, Scheffner M, Del Sal G (1999) Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J 18(22):6462–6471. doi:10.1093/emboj/18.22.6462
Guzzo CM, Berndsen CE, Zhu J, Gupta V, Datta A, Greenberg RA, Wolberger C, Matunis MJ (2012) RNF4-dependent hybrid SUMO-ubiquitin chains are signals for RAP80 and thereby mediate the recruitment of BRCA1 to sites of DNA damage. Sci Signal 5(253):ra88. doi:10.1126/scisignal.2003485
Haindl M, Harasim T, Eick D, Muller S (2008) The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing. EMBO Rep 9(3):273–279. doi:10.1038/embor.2008.3
Henras AK, Soudet J, Gerus M, Lebaron S, Caizergues-Ferrer M, Mougin A, Henry Y (2008) The post-transcriptional steps of eukaryotic ribosome biogenesis. Cell Mol Life Sci: CMLS 65(15):2334–2359. doi:10.1007/s00018-008-8027-0
Heun P (2007) SUMOrganization of the nucleus. Curr Opin Cell Biol 19(3):350–355. doi:10.1016/j.ceb.2007.04.014
Hickey CM, Wilson NR, Hochstrasser M (2012) Function and regulation of SUMO proteases. Nat Rev Mol Cell Biol 13(12):755–766. doi:10.1038/nrm3478
Huang W, Ghisletti S, Saijo K, Gandhi M, Aouadi M, Tesz GJ, Zhang DX, Yao J, Czech MP, Goode BL, Rosenfeld MG, Glass CK (2011) Coronin 2A mediates actin-dependent de-repression of inflammatory response genes. Nature 470(7334):414–418. doi:10.1038/nature09703
Husnjak K, Dikic I (2012) Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem 81:291–322. doi:10.1146/annurev-biochem-051810-094654
Jackson SP, Durocher D (2013) Regulation of DNA damage responses by ubiquitin and SUMO. Mol Cell 49(5):795–807. doi:10.1016/j.molcel.2013.01.017
Kim J, Cantwell CA, Johnson PF, Pfarr CM, Williams SC (2002) Transcriptional activity of CCAAT/enhancer-binding proteins is controlled by a conserved inhibitory domain that is a target for sumoylation. J Biol Chem 277(41):38037–38044. doi:10.1074/jbc.M207235200
Kressler D, Hurt E, Bassler J (2010) Driving ribosome assembly. Biochim Biophys Acta 1803(6):673–683. doi:10.1016/j.bbamcr.2009.10.009
Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, Zhou J, Zhu J, Raught B, de The H (2008) Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol 10(5):547–555. doi:10.1038/ncb1717
Lee JH, Park SM, Kim OS, Lee CS, Woo JH, Park SJ, Joe EH, Jou I (2009) Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes. Mol Cell 35(6):806–817. doi:10.1016/j.molcel.2009.07.021
Lehembre F, Muller S, Pandolfi PP, Dejean A (2001) Regulation of Pax3 transcriptional activity by SUMO-1-modified PML. Oncogene 20(1):1–9. doi:10.1038/sj.onc.1204063
Li H, Leo C, Zhu J, Wu X, O’Neil J, Park EJ, Chen JD (2000) Sequestration and inhibition of Daxx-mediated transcriptional repression by PML. Mol Cell Biol 20(5):1784–1796
Lin DY, Huang YS, Jeng JC, Kuo HY, Chang CC, Chao TT, Ho CC, Chen YC, Lin TP, Fang HI, Hung CC, Suen CS, Hwang MJ, Chang KS, Maul GG, Shih HM (2006) Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol Cell 24(3):341–354. doi:10.1016/j.molcel.2006.10.019
Liu Y, Bridges R, Wortham A, Kulesz-Martin M (2012a) NF-kappaB repression by PIAS3 mediated RelA SUMOylation. PLoS One 7(5):e37636. doi:10.1371/journal.pone.0037636
Liu HW, Zhang J, Heine GF, Arora M, Gulcin Ozer H, Onti-Srinivasan R, Huang K, Parvin JD (2012b) Chromatin modification by SUMO-1 stimulates the promoters of translation machinery genes. Nucleic Acids Res 40(20):10172–10186. doi:10.1093/nar/gks819
Maison C, Bailly D, Roche D, Montes de Oca R, Probst AV, Vassias I, Dingli F, Lombard B, Loew D, Quivy JP, Almouzni G (2011) SUMOylation promotes de novo targeting of HP1alpha to pericentric heterochromatin. Nat Genet 43(3):220–227. doi:10.1038/ng.765
Mao YS, Zhang B, Spector DL (2011) Biogenesis and function of nuclear bodies. Trends Genet 27(8):295–306. doi:10.1016/j.tig.2011.05.006
Martin N, Schwamborn K, Schreiber V, Werner A, Guillier C, Zhang XD, Bischof O, Seeler JS, Dejean A (2009) PARP-1 transcriptional activity is regulated by sumoylation upon heat shock. EMBO J 28(22):3534–3548. doi:10.1038/emboj.2009.279
Matic I, Schimmel J, Hendriks IA, van Santen MA, van de Rijke F, van Dam H, Gnad F, Mann M, Vertegaal AC (2010) Site-specific identification of SUMO-2 targets in cells reveals an inverted SUMOylation motif and a hydrophobic cluster SUMOylation motif. Mol Cell 39(4):641–652. doi:10.1016/j.molcel.2010.07.026
Matunis MJ, Zhang XD, Ellis NA (2006) SUMO: the glue that binds. Dev Cell 11(5):596–597. doi:10.1016/j.devcel.2006.10.011
Messner S, Schuermann D, Altmeyer M, Kassner I, Schmidt D, Schar P, Muller S, Hottiger MO (2009) Sumoylation of poly(ADP-ribose) polymerase 1 inhibits its acetylation and restrains transcriptional coactivator function. FASEB J 23(11):3978–3989. doi:10.1096/fj.09-137695
Miller MJ, Scalf M, Rytz TC, Hubler SL, Smith LM, Vierstra RD (2013) Quantitative proteomics reveals factors regulating RNA biology as dynamic targets of stress-induced SUMOylation in Arabidopsis. Mol Cell Proteomics : MCP 12(2):449–463. doi:10.1074/mcp.M112.025056
Morris JR, Boutell C, Keppler M, Densham R, Weekes D, Alamshah A, Butler L, Galanty Y, Pangon L, Kiuchi T, Ng T, Solomon E (2009) The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature 462(7275):886–890. doi:10.1038/nature08593
Mukhopadhyay D, Matunis MJ (2011) SUMmOning Daxx-mediated repression. Mol Cell 42(1):4–5. doi:10.1016/j.molcel.2011.03.008
Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean A (2000) c-Jun and p53 activity is modulated by SUMO-1 modification. J Biol Chem 275(18):13321–13329
Muller S, Matunis MJ, Dejean A (1998) Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J 17(1):61–70. doi:10.1093/emboj/17.1.61
Ouyang J, Gill G (2009) SUMO engages multiple corepressors to regulate chromatin structure and transcription. Epigenetics: Off J DNA Methylation Soc 4(7):440–444
Ouyang J, Shi Y, Valin A, Xuan Y, Gill G (2009) Direct binding of CoREST1 to SUMO-2/3 contributes to gene-specific repression by the LSD1/CoREST1/HDAC complex. Mol Cell 34(2):145–154. doi:10.1016/j.molcel.2009.03.013
Panse VG, Hardeland U, Werner T, Kuster B, Hurt E (2004) A proteome-wide approach identifies sumoylated substrate proteins in yeast. J Biol Chem 279(40):41346–41351. doi:10.1074/jbc.M407950200
Panse VG, Kressler D, Pauli A, Petfalski E, Gnadig M, Tollervey D, Hurt E (2006) Formation and nuclear export of preribosomes are functionally linked to the small-ubiquitin-related modifier pathway. Traffic 7(10):1311–1321. doi:10.1111/j.1600-0854.2006.00471.x
Park HC, Choi W, Park HJ, Cheong MS, Koo YD, Shin G, Chung WS, Kim WY, Kim MG, Bressan RA, Bohnert HJ, Lee SY, Yun DJ (2011) Identification and molecular properties of SUMO-binding proteins in Arabidopsis. Mol Cells 32(2):143–151. doi:10.1007/s10059-011-2297-3
Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, Rose DW, Willson TM, Rosenfeld MG, Glass CK (2005) A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437(7059):759–763. doi:10.1038/nature03988
Patel DJ, Wang Z (2013) Readout of epigenetic modifications. Annu Rev Biochem. doi:10.1146/annurev-biochem-072711-165700
Psakhye I, Jentsch S (2012) Protein group modification and synergy in the SUMO pathway as exemplified in DNA repair. Cell 151(4):807–820. doi:10.1016/j.cell.2012.10.021
Rodriguez MS, Desterro JM, Lain S, Midgley CA, Lane DP, Hay RT (1999) SUMO-1 modification activates the transcriptional response of p53. EMBO J 18(22):6455–6461. doi:10.1093/emboj/18.22.6455
Rosonina E, Duncan SM, Manley JL (2010) SUMO functions in constitutive transcription and during activation of inducible genes in yeast. Genes Dev 24(12):1242–1252. doi:10.1101/gad.1917910
Rosonina E, Duncan SM, Manley JL (2012) Sumoylation of transcription factor Gcn4 facilitates its Srb10-mediated clearance from promoters in yeast. Genes Dev 26(4):350–355. doi:10.1101/gad.184689.111
Ross S, Best JL, Zon LI, Gill G (2002) SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization. Mol Cell 10(4):831–842
Sun H, Hunter T (2012) Poly-small ubiquitin-like modifier (PolySUMO)-binding proteins identified through a string search. J Biol Chem 287(50):42071–42083. doi:10.1074/jbc.M112.410985
Sapetschnig A, Rischitor G, Braun H, Doll A, Schergaut M, Melchior F, Suske G (2002) Transcription factor Sp3 is silenced through SUMO modification by PIAS1. EMBO J 21(19):5206–5215
Seet BT, Dikic I, Zhou MM, Pawson T (2006) Reading protein modifications with interaction domains. Nat Rev Mol Cell Biol 7(7):473–483. doi:10.1038/nrm1960
Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP (2006) The mechanisms of PML-nuclear body formation. Mol Cell 24(3):331–339. doi:10.1016/j.molcel.2006.09.013
Stehmeier P, Muller S (2009a) Phospho-regulated SUMO interaction modules connect the SUMO system to CK2 signaling. Mol Cell 33(3):400–409. doi:10.1016/j.molcel.2009.01.013
Stehmeier P, Muller S (2009b) Regulation of p53 family members by the ubiquitin-like SUMO system. DNA Repair 8(4):491–498. doi:10.1016/j.dnarep.2009.01.002
Stielow B, Kruger I, Diezko R, Finkernagel F, Gillemans N, Kong-a-San J, Philipsen S, Suske G (2010) Epigenetic silencing of spermatocyte-specific and neuronal genes by SUMO modification of the transcription factor Sp3. PLoS Genet 6(11):e1001203. doi:10.1371/journal.pgen.1001203
Stielow B, Sapetschnig A, Kruger I, Kunert N, Brehm A, Boutros M, Suske G (2008a) Identification of SUMO-dependent chromatin-associated transcriptional repression components by a genome-wide RNAi screen. Mol Cell 29(6):742–754. doi:10.1016/j.molcel.2007.12.032
Stielow B, Sapetschnig A, Wink C, Kruger I, Suske G (2008b) SUMO-modified Sp3 represses transcription by provoking local heterochromatic gene silencing. EMBO Rep 9(9):899–906. doi:10.1038/embor.2008.127
Tanaka N, Saitoh H (2010) A real-time SUMO-binding assay for the analysis of the SUMO-SIM protein interaction network. Biosci Biotechnol Biochem 74(6):1302–1305
Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT (2008) RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol 10(5):538–546. doi:10.1038/ncb1716
Tatham MH, Matic I, Mann M, Hay RT (2011) Comparative proteomic analysis identifies a role for SUMO in protein quality control. Sci Signal 4(178):rs4. doi:10.1126/scisignal.2001484
Tempe D, Vives E, Brockly F, Brooks H, De Rossi S, Piechaczyk M, Bossis G (2013) SUMOylation of the inducible (c-Fos:c-Jun)/AP-1 transcription complex occurs on target promoters to limit transcriptional activation. Oncogene. doi:10.1038/onc.2013.4
Treuter E, Venteclef N (2011) Transcriptional control of metabolic and inflammatory pathways by nuclear receptor SUMOylation. Biochim Biophys Acta 1812(8):909–918. doi:10.1016/j.bbadis.2010.12.008
Uchimura Y, Ichimura T, Uwada J, Tachibana T, Sugahara S, Nakao M, Saitoh H (2006) Involvement of SUMO modification in MBD1- and MCAF1-mediated heterochromatin formation. J Biol Chem 281(32):23180–23190. doi:10.1074/jbc.M602280200
Ullmann R, Chien CD, Avantaggiati ML, Muller S (2012) An acetylation switch regulates SUMO-dependent protein interaction networks. Mol Cell 46(6):759–770. doi:10.1016/j.molcel.2012.04.006
Ulrich HD (2008) The fast-growing business of SUMO chains. Mol Cell 32(3):301–305. doi:10.1016/j.molcel.2008.10.010
van der Veen AG, Ploegh HL (2012) Ubiquitin-like proteins. Annu Rev Biochem 81:323–357. doi:10.1146/annurev-biochem-093010-153308
Venteclef N, Jakobsson T, Ehrlund A, Damdimopoulos A, Mikkonen L, Ellis E, Nilsson LM, Parini P, Janne OA, Gustafsson JA, Steffensen KR, Treuter E (2010) GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRbeta in the hepatic acute phase response. Genes Dev 24(4):381–395. doi:10.1101/gad.545110
Vertegaal AC, Ogg SC, Jaffray E, Rodriguez MS, Hay RT, Andersen JS, Mann M, Lamond AI (2004) A proteomic study of SUMO-2 target proteins. J Biol Chem 279(32):33791–33798. doi:10.1074/jbc.M404201200
Wei W, Yang P, Pang J, Zhang S, Wang Y, Wang MH, Dong Z, She JX, Wang CY (2008) A stress-dependent SUMO4 sumoylation of its substrate proteins. Biochem Biophys Res Commun 375(3):454–459. doi:10.1016/j.bbrc.2008.08.028
Westman BJ, Verheggen C, Hutten S, Lam YW, Bertrand E, Lamond AI (2010) A proteomic screen for nucleolar SUMO targets shows SUMOylation modulates the function of Nop5/Nop58. Mol Cell 39(4):618–631. doi:10.1016/j.molcel.2010.07.025
Westman BJ, Lamond AI (2011) A role for SUMOylation in snoRNP biogenesis revealed by quantitative proteomics. Nucleus 2(1):30–37. doi:10.4161/nucl.2.1.14437
Wilkinson KA, Henley JM (2010) Mechanisms, regulation and consequences of protein SUMOylation. Biochem J 428(2):133–145. doi:10.1042/BJ20100158
Wu SY, Chiang CM (2009) Crosstalk between sumoylation and acetylation regulates p53-dependent chromatin transcription and DNA binding. EMBO J 28(9):1246–1259. doi:10.1038/emboj.2009.83
Yin Y, Seifert A, Chua JS, Maure JF, Golebiowski F, Hay RT (2012) SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage. Genes Dev 26(11):1196–1208. doi:10.1101/gad.189274.112
Yun C, Wang Y, Mukhopadhyay D, Backlund P, Kolli N, Yergey A, Wilkinson KD, Dasso M (2008) Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases. J Cell Biol 183(4):589–595. doi:10.1083/jcb.200807185
Zhong S, Muller S, Ronchetti S, Freemont PS, Dejean A, Pandolfi PP (2000) Role of SUMO-1-modified PML in nuclear body formation. Blood 95(9):2748–2752
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This work was supported by the “Deutsche Forschungsgemeinschaft” SPP1365. We thank all members of our lab for the critical reading and helpful discussions. We apologize to all authors whose original papers could not be cited due to space limitations.
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Nithya Raman and Arnab Nayak contributed equally to this manuscript.
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Raman, N., Nayak, A. & Muller, S. The SUMO system: a master organizer of nuclear protein assemblies. Chromosoma 122, 475–485 (2013). https://doi.org/10.1007/s00412-013-0429-6
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DOI: https://doi.org/10.1007/s00412-013-0429-6