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• W2885330316 abstract "Since the discovery of SUMO twenty years ago, SUMO conjugation has become a widely recognized post-translational modification that targets a myriad of proteins in many processes. Great progress has been made in understanding the SUMO pathway enzymes, substrate sumoylation, and the interplay between sumoylation and other regulatory mechanisms in a variety of contexts. As these research directions continue to generate insights into SUMO-based regulation, several mechanisms by which sumoylation and desumoylation can orchestrate large biological effects are emerging. These include the ability to target multiple proteins within the same cellular structure or process, respond dynamically to external and internal stimuli, and modulate signaling pathways involving other post-translational modifications. Focusing on nuclear function and intracellular signaling, this review highlights a broad spectrum of historical data and recent advances with the aim of providing an overview of mechanisms underlying SUMO-mediated global effects to stimulate further inquiry into intriguing roles of SUMO. Since the discovery of SUMO twenty years ago, SUMO conjugation has become a widely recognized post-translational modification that targets a myriad of proteins in many processes. Great progress has been made in understanding the SUMO pathway enzymes, substrate sumoylation, and the interplay between sumoylation and other regulatory mechanisms in a variety of contexts. As these research directions continue to generate insights into SUMO-based regulation, several mechanisms by which sumoylation and desumoylation can orchestrate large biological effects are emerging. These include the ability to target multiple proteins within the same cellular structure or process, respond dynamically to external and internal stimuli, and modulate signaling pathways involving other post-translational modifications. Focusing on nuclear function and intracellular signaling, this review highlights a broad spectrum of historical data and recent advances with the aim of providing an overview of mechanisms underlying SUMO-mediated global effects to stimulate further inquiry into intriguing roles of SUMO. SUMO proteins are a family of conserved eukaryotic protein modifiers of approximately 100 amino acids. SUMO conjugation to the lysine(s) of substrates is carried out by SUMO E1, E2, and E3 enzymes (Johnson, 2004Johnson E.S. Protein modification by SUMO.Annu. Rev. Biochem. 2004; 73: 355-382Crossref PubMed Scopus (1216) Google Scholar). Organisms examined so far contain only a single SUMO E1 and E2 enzyme but multiple SUMO E3 enzymes. The SUMO E1 uses ATP hydrolysis to covalently link SUMO to its active-site cysteine and subsequently transfer SUMO to the active site on the E2. With the help of a SUMO E3 (or ligase), the E2 further transfers SUMO onto substrates (Figure 1A). SUMO is often conjugated at the sumoylation consensus sequence, ψKxE/D (ψ, hydrophobic residues; x, any amino acid; K, sumoylation site), which is recognized by the E2, or its reverse sequence (Rodriguez et al., 2001Rodriguez M.S. Dargemont C. Hay R.T. SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting.J. Biol. Chem. 2001; 276: 12654-12659Crossref PubMed Scopus (528) Google Scholar, Sampson et al., 2001Sampson D.A. Wang M. Matunis M.J. 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: 21664-21669Crossref PubMed Scopus (339) Google Scholar). SUMO E3s support productive configurations for SUMO transfer by simultaneously binding the SUMO-charged E2 and the substrate (Streich and Lima, 2016Streich Jr., F.C. Lima C.D. Capturing a substrate in an activated RING E3/E2-SUMO complex.Nature. 2016; 536: 304-308Crossref PubMed Google Scholar, Werner et al., 2012Werner A. Flotho A. Melchior F. The RanBP2/RanGAP1∗SUMO1/Ubc9 complex is a multisubunit SUMO E3 ligase.Mol. Cell. 2012; 46: 287-298Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). The multiple SUMO E3s within a cell have both distinct and overlapping substrates (Pichler et al., 2017Pichler A. Fatouros C. Lee H. Eisenhardt N. SUMO conjugation - a mechanistic view.Biomol. Concepts. 2017; 8: 13-36Crossref PubMed Scopus (0) Google Scholar). While lower eukaryotes contain only one SUMO, higher eukaryotes possess at least three SUMO isoforms, namely SUMO1–3. These isoforms differ in several respects, such as in their SUMO E3 preferences or ability to form poly-SUMO chains by conjugation of one SUMO to another SUMO molecule via different lysine residues (Pichler et al., 2017Pichler A. Fatouros C. Lee H. Eisenhardt N. SUMO conjugation - a mechanistic view.Biomol. Concepts. 2017; 8: 13-36Crossref PubMed Scopus (0) Google Scholar). Cell line studies further suggest that while the majority of SUMO1 is conjugated to substrates, SUMO2/3 mostly becomes conjugated under stress conditions. These differences suggest that SUMO isoforms can have distinct functions and regulation. Once conjugated to substrates, SUMO can exert a variety of effects. These include changing substrate interactions with DNA, RNA, or other proteins, altering conformation or enzymatic activities, and modulating other modifications (Flotho and Melchior, 2013Flotho A. Melchior F. Sumoylation: a regulatory protein modification in health and disease.Annu. Rev. Biochem. 2013; 82: 357-385Crossref PubMed Scopus (457) Google Scholar). Among these effects, the most frequently described has been interactions between SUMO and SUMO interaction motifs (SIMs). Canonical SIMs contain a core of hydrophobic residues preceded or followed by negatively charged amino acids; they contact a hydrophobic pocket on SUMO with neighboring basic residues (Hecker et al., 2006Hecker C.M. Rabiller M. Haglund K. Bayer P. Dikic I. Specification of SUMO1- and SUMO2-interacting motifs.J. Biol. Chem. 2006; 281: 16117-16127Crossref PubMed Scopus (361) Google Scholar, Song et al., 2004Song J. Durrin L.K. Wilkinson T.A. Krontiris T.G. Chen Y. Identification of a SUMO-binding motif that recognizes SUMO-modified proteins.Proc. Natl. Acad. Sci. USA. 2004; 101: 14373-14378Crossref PubMed Scopus (396) Google Scholar). The SUMO:SIM association is generally weak but can be enhanced by the binding of multiple SIMs to SUMO chains. Effects of sumoylation can be reversed when the modification is removed by SUMO-specific proteases, or desumoylases, which are also functionally important (Hickey et al., 2012Hickey C.M. Wilson N.R. Hochstrasser M. Function and regulation of SUMO proteases.Nat. Rev. Mol. Cell Biol. 2012; 13: 755-766Crossref PubMed Scopus (289) Google Scholar) (Figure 1A). In the early 2000s, examination of SUMO and sumoylation machinery mutants captured some striking nuclear structural defects, such as fragmented nucleoli, declustered telomeres, and heterochromatin breakdown (Hari et al., 2001Hari 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. 2001; 15: 1334-1348Crossref PubMed Scopus (137) Google Scholar, Nacerddine et al., 2005Nacerddine K. Lehembre F. Bhaumik M. Artus J. Cohen-Tannoudji M. Babinet C. Pandolfi P.P. Dejean A. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice.Dev. Cell. 2005; 9: 769-779Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, Shin et al., 2005Shin J.A. Choi E.S. Kim H.S. Ho J.C. Watts F.Z. Park S.D. Jang Y.K. SUMO modification is involved in the maintenance of heterochromatin stability in fission yeast.Mol. Cell. 2005; 19: 817-828Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, Xhemalce et al., 2004Xhemalce B. Seeler J.S. Thon G. Dejean A. Arcangioli B. Role of the fission yeast SUMO E3 ligase Pli1p in centromere and telomere maintenance.EMBO J. 2004; 23: 3844-3853Crossref PubMed Scopus (0) Google Scholar, Zhao and Blobel, 2005Zhao X. Blobel G. A SUMO ligase is part of a nuclear multiprotein complex that affects DNA repair and chromosomal organization.Proc. Natl. Acad. Sci. USA. 2005; 102: 4777-4782Crossref PubMed Scopus (300) Google Scholar). Meanwhile, SUMO enzymes and sumoylated proteins were found to be enriched at nuclear structures, such as PML (promyelocytic leukemia) and Polycomb bodies (Kagey et al., 2003Kagey M.H. Melhuish T.A. Wotton D. The polycomb protein Pc2 is a SUMO E3.Cell. 2003; 113: 127-137Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar, Müller et al., 1998Müller S. Matunis M.J. Dejean A. Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus.EMBO J. 1998; 17: 61-70Crossref PubMed Scopus (552) Google Scholar, Sternsdorf et al., 1997Sternsdorf T. Jensen K. Will H. Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1.J. Cell Biol. 1997; 139: 1621-1634Crossref PubMed Scopus (0) Google Scholar). These early findings hinted at the possibility that SUMO may globally affect biological processes via modulation of nuclear structures. Indeed, insights into cellular membraneless structures suggest that SUMO’s ability to facilitate protein-protein interactions can contribute to their formation. In general, proteins capable of intra- or inter-molecular multivalent interactions can form large oligomers and phase separate from the surrounding solution (Banani et al., 2017Banani S.F. Lee H.O. Hyman A.A. Rosen M.K. Biomolecular condensates: organizers of cellular biochemistry.Nat. Rev. Mol. Cell Biol. 2017; 18: 285-298Crossref PubMed Scopus (543) Google Scholar, Hyman et al., 2014Hyman A.A. Weber C.A. Jülicher F. Liquid-liquid phase separation in biology.Annu. Rev. Cell Dev. Biol. 2014; 30: 39-58Crossref PubMed Google Scholar). These proteins can then use their modular interaction domains or intrinsically disordered regions to recruit additional macro-molecules, expanding liquid droplets. These droplets and membraneless structures can undergo fusion, fission, and rapid molecular exchange with the surrounding solution, yet high concentrations of macro-molecules within the structures may promote certain biological processes (Banani et al., 2017Banani S.F. Lee H.O. Hyman A.A. Rosen M.K. Biomolecular condensates: organizers of cellular biochemistry.Nat. Rev. Mol. Cell Biol. 2017; 18: 285-298Crossref PubMed Scopus (543) Google Scholar). PML bodies provide an example of how SUMO:SIM interactions could contribute to the phase separation-mediated formation of nuclear structures. PML bodies host more than 150 proteins with a wide range of functions, such as DNA repair, stress response, senescence, anti-viral immunity, and tumor suppression (Sahin et al., 2014Sahin U. de Thé H. Lallemand-Breitenbach V. PML nuclear bodies: assembly and oxidative stress-sensitive sumoylation.Nucleus. 2014; 5: 499-507Crossref PubMed Scopus (38) Google Scholar). These proteins appear to carry out some of their roles within PML bodies, though a unifying model for PML body functions remains to be established (Lallemand-Breitenbach and de Thé, 2018Lallemand-Breitenbach V. de Thé H. PML nuclear bodies: from architecture to function.Curr. Opin. Cell Biol. 2018; 52: 154-161Crossref PubMed Scopus (0) Google Scholar). It was noted early on that PML proteins and many other PML body constituents are sumoylated and contain SIMs; importantly, mutations affecting their sumoylation or SIMs were shown to impair PML body formation or constituent recruitment (Sahin et al., 2014Sahin U. de Thé H. Lallemand-Breitenbach V. PML nuclear bodies: assembly and oxidative stress-sensitive sumoylation.Nucleus. 2014; 5: 499-507Crossref PubMed Scopus (38) Google Scholar, Shen et al., 2006Shen T.H. Lin H.K. Scaglioni P.P. Yung T.M. Pandolfi P.P. The mechanisms of PML-nuclear body formation.Mol. Cell. 2006; 24: 805Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). These findings and additional data suggest a model for PML body formation, wherein sumoylation of self-associated PML proteins recruits SIM-containing partner proteins, and sumoylation of the latter leads to additional SUMO:SIM interactions and PML body expansion (Banani et al., 2017Banani S.F. Lee H.O. Hyman A.A. Rosen M.K. Biomolecular condensates: organizers of cellular biochemistry.Nat. Rev. Mol. Cell Biol. 2017; 18: 285-298Crossref PubMed Scopus (543) Google Scholar, Sahin et al., 2014Sahin U. de Thé H. Lallemand-Breitenbach V. PML nuclear bodies: assembly and oxidative stress-sensitive sumoylation.Nucleus. 2014; 5: 499-507Crossref PubMed Scopus (38) Google Scholar, Wang et al., 2018Wang P. Benhenda S. Wu H. Lallemand-Breitenbach V. Zhen T. Jollivet F. Peres L. Li Y. Chen S.-J. Chen Z. et al.RING tetramerization is required for nuclear body biogenesis and PML sumoylation.Nat. Commun. 2018; 9: 1277Crossref PubMed Scopus (1) Google Scholar). Modeling SUMO:SIM interactions in engineered proteins shows that they are sufficient for driving phase separation in vitro, providing strong support for this model (Banani et al., 2016Banani S.F. Rice A.M. Peeples W.B. Lin Y. Jain S. Parker R. Rosen M.K. Compositional control of phase-separated cellular bodies.Cell. 2016; 166: 651-663Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). The nucleolus is the site of ribosome assembly, RNA processing, and cell cycle regulation, among other functions. Its domains also exhibit liquid droplet-like behaviors, such as diffusion and fusion (Brangwynne et al., 2011Brangwynne C.P. Mitchison T.J. Hyman A.A. Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes.Proc. Natl. Acad. Sci. USA. 2011; 108: 4334-4339Crossref PubMed Scopus (357) Google Scholar, Feric et al., 2016Feric M. Vaidya N. Harmon T.S. Mitrea D.M. Zhu L. Richardson T.M. Kriwacki R.W. Pappu R.V. Brangwynne C.P. Coexisting liquid phases underlie nucleolar subcompartments.Cell. 2016; 165: 1686-1697Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar). How SUMO affects these behaviors has not been directly interrogated, but sumoylation and desumoylation both influence nucleolar structure and function. On one hand, nucleoli contain a proportion of sumoylation enzymes and substrates, and some of these enzymes and sumoylation events promote nucleolar integrity and functions (Ayaydin and Dasso, 2004Ayaydin F. Dasso M. Distinct in vivo dynamics of vertebrate SUMO paralogues.Mol. Biol. Cell. 2004; 15: 5208-5218Crossref PubMed Scopus (147) Google Scholar, Heun, 2007Heun P. SUMOrganization of the nucleus.Curr. Opin. Cell Biol. 2007; 19: 350-355Crossref PubMed Scopus (118) Google Scholar, Matafora et al., 2009Matafora V. D’Amato A. Mori S. Blasi F. Bachi A. Proteomics analysis of nucleolar SUMO-1 target proteins upon proteasome inhibition.Mol. Cell. Proteomics. 2009; 8: 2243-2255Crossref PubMed Scopus (64) Google Scholar, Srikumar et al., 2013Srikumar T. Lewicki M.C. Raught B. A global S. cerevisiae small ubiquitin-related modifier (SUMO) system interactome.Mol. Syst. Biol. 2013; 9: 668Crossref PubMed Scopus (0) Google Scholar, Takahashi et al., 2008Takahashi Y. Dulev S. Liu X. Hiller N.J. Zhao X. Strunnikov A. Cooperation of sumoylated chromosomal proteins in rDNA maintenance.PLoS Genet. 2008; 4: e1000215Crossref PubMed Scopus (51) Google Scholar, Westman et al., 2010Westman B.J. Verheggen C. Hutten S. Lam Y.W. Bertrand E. Lamond A.I. A proteomic screen for nucleolar SUMO targets shows SUMOylation modulates the function of Nop5/Nop58.Mol. Cell. 2010; 39: 618-631Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Zhao and Blobel, 2005Zhao X. Blobel G. A SUMO ligase is part of a nuclear multiprotein complex that affects DNA repair and chromosomal organization.Proc. Natl. Acad. Sci. USA. 2005; 102: 4777-4782Crossref PubMed Scopus (300) Google Scholar). On the other hand, desumoylation enzymes such as SENP3 and 5 that target SUMO2/3 conjugates are also enriched in nucleoli and are required for nucleolar function (Di Bacco et al., 2006Di Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. The SUMO-specific protease SENP5 is required for cell division.Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (0) Google Scholar, Finkbeiner et al., 2011Finkbeiner E. Haindl M. Raman N. Muller S. SUMO routes ribosome maturation.Nucleus. 2011; 2: 527-532Crossref PubMed Scopus (29) Google Scholar, Liang et al., 2017Liang J. Singh N. Carlson C.R. Albuquerque C.P. Corbett K.D. Zhou H. Recruitment of a SUMO isopeptidase to rDNA stabilizes silencing complexes by opposing SUMO targeted ubiquitin ligase activity.Genes Dev. 2017; 31: 802-815Crossref PubMed Scopus (15) Google Scholar, Yun et al., 2008Yun C. Wang Y. Mukhopadhyay D. Backlund P. Kolli N. Yergey A. Wilkinson K.D. Dasso M. Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases.J. Cell Biol. 2008; 183: 589-595Crossref PubMed Scopus (0) Google Scholar). These data may suggest that specific sumoylation events and balanced sumoylation levels are required for nucleolar biology. Nucleoli additionally contain abundant ribosomal DNA units and RNA species capable of macromolecular association. A productive line of future inquiry may be exploring the potential collaborations between these DNA/RNA molecules and SUMO in sculpting nucleoli. While SUMO helps to “build up” membraneless organelles, it can also “break down” inactive proteinaceous structures, some of which underlie neurodegenerative diseases. A few examples include the ability of sumoylation to prevent protein inclusions formed by the transcriptional corepressor subunit Cyc8, to solubilize DNA end-resection protein Sae2, and to reduce aggregation of translation factor CPEB3 or transcription factor androgen receptor (Drisaldi et al., 2015Drisaldi B. Colnaghi L. Fioriti L. Rao N. Myers C. Snyder A.M. Metzger D.J. Tarasoff J. Konstantinov E. Fraser P.E. et al.SUMOylation is an inhibitory constraint that regulates the prion-like aggregation and activity of CPEB3.Cell Rep. 2015; 11: 1694-1702Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, Mukherjee et al., 2009Mukherjee S. Thomas M. Dadgar N. Lieberman A.P. Iñiguez-Lluhí J.A. Small ubiquitin-like modifier (SUMO) modification of the androgen receptor attenuates polyglutamine-mediated aggregation.J. Biol. Chem. 2009; 284: 21296-21306Crossref PubMed Scopus (65) Google Scholar, Oeser et al., 2016Oeser M.L. Amen T. Nadel C.M. Bradley A.I. Reed B.J. Jones R.D. Gopalan J. Kaganovich D. Gardner R.G. Dynamic sumoylation of a conserved transcription corepressor prevents persistent inclusion formation during hyperosmotic stress.PLoS Genet. 2016; 12: e1005809Crossref PubMed Scopus (7) Google Scholar, Sarangi et al., 2015Sarangi P. Steinacher R. Altmannova V. Fu Q. Paull T.T. Krejci L. Whitby M.C. Zhao X. Sumoylation influences DNA break repair partly by increasing the solubility of a conserved end resection protein.PLoS Genet. 2015; 11: e1004899Crossref PubMed Google Scholar). Future study on how SUMO contributes to the dynamic assembly and disassembly of other proteinaceous and membraneless structures will expand our understanding of the structural roles of SUMO. SUMO and SUMO pathway enzymes associate with chromatin, and SUMO substrates are enriched among DNA-binding proteins (Chymkowitch et al., 2015Chymkowitch P. Nguéa A.P. Aanes H. Koehler C.J. Thiede B. Lorenz S. Meza-Zepeda L.A. Klungland A. Enserink J.M. Sumoylation of Rap1 mediates the recruitment of TFIID to promote transcription of ribosomal protein genes.Genome Res. 2015; 25: 897-906Crossref PubMed Scopus (27) Google Scholar, Flotho and Melchior, 2013Flotho A. Melchior F. Sumoylation: a regulatory protein modification in health and disease.Annu. Rev. Biochem. 2013; 82: 357-385Crossref PubMed Scopus (457) Google Scholar, Hendriks and Vertegaal, 2016Hendriks I.A. Vertegaal A.C.O. A comprehensive compilation of SUMO proteomics.Nat. Rev. Mol. Cell Biol. 2016; 17: 581-595Crossref PubMed Scopus (142) Google Scholar, Neyret-Kahn et al., 2013Neyret-Kahn H. Benhamed M. Ye T. Le Gras S. Cossec J.C. Lapaquette P. Bischof O. Ouspenskaia M. Dasso M. Seeler J. et al.Sumoylation at chromatin governs coordinated repression of a transcriptional program essential for cell growth and proliferation.Genome Res. 2013; 23: 1563-1579Crossref PubMed Scopus (64) Google Scholar, Niskanen et al., 2015Niskanen E.A. Malinen M. Sutinen P. Toropainen S. Paakinaho V. Vihervaara A. Joutsen J. Kaikkonen M.U. Sistonen L. Palvimo J.J. Global SUMOylation on active chromatin is an acute heat stress response restricting transcription.Genome Biol. 2015; 16: 153Crossref PubMed Scopus (31) Google Scholar). These observations corroborate early genetic data that SUMO deficiency drastically changes chromosome integrity and segregation (Hari et al., 2001Hari 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. 2001; 15: 1334-1348Crossref PubMed Scopus (137) Google Scholar, Nacerddine et al., 2005Nacerddine K. Lehembre F. Bhaumik M. Artus J. Cohen-Tannoudji M. Babinet C. Pandolfi P.P. Dejean A. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice.Dev. Cell. 2005; 9: 769-779Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, Shin et al., 2005Shin J.A. Choi E.S. Kim H.S. Ho J.C. Watts F.Z. Park S.D. Jang Y.K. SUMO modification is involved in the maintenance of heterochromatin stability in fission yeast.Mol. Cell. 2005; 19: 817-828Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, Tanaka et al., 1999Tanaka K. Nishide J. Okazaki K. Kato H. Niwa O. Nakagawa T. Matsuda H. Kawamukai M. Murakami Y. 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: 8660-8672Crossref PubMed Scopus (147) Google Scholar, Xhemalce et al., 2004Xhemalce B. Seeler J.S. Thon G. Dejean A. Arcangioli B. Role of the fission yeast SUMO E3 ligase Pli1p in centromere and telomere maintenance.EMBO J. 2004; 23: 3844-3853Crossref PubMed Scopus (0) Google Scholar). Recent studies further elucidated how dynamic sumoylation regulates specific chromosome structures, such as centromeres, telomeres, heterochromatin, and broken regions, as summarized below (Figure 1B). Centromeres contain specialized histones and silenced chromatin and support the assembly of kinetochores for microtubule attachment during mitosis. SUMO pathway enzymes are enriched at centromeres and kinetochores in multiple organisms, and sumoylation of numerous proteins concertedly regulates centromeric structure and function, as reviewed recently (Cubeñas-Potts and Matunis, 2013Cubeñas-Potts C. Matunis M.J. SUMO: a multifaceted modifier of chromatin structure and function.Dev. Cell. 2013; 24: 1-12Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). One highly conserved SUMO substrate is Topoisomerase II (or Top2) (Clarke and Azuma, 2017Clarke D.J. Azuma Y. Non-Catalytic Roles of the Topoisomerase IIα C-Terminal Domain.Int. J. Mol. Sci. 2017; 18: E2438Crossref PubMed Scopus (3) Google Scholar). Sumoylation of the Top2 C-terminal non-catalytic region leads to centromeric recruitment of Top2 itself to decatenate intertwined DNA before anaphase as well as other mitotic factors (Claspin, Haspin, and Aurora B kinases) to promote centromeric segregation (Azuma et al., 2003Azuma Y. Arnaoutov A. Dasso M. SUMO-2/3 regulates topoisomerase II in mitosis.J. Cell Biol. 2003; 163: 477-487Crossref PubMed Scopus (160) Google Scholar, Bachant et al., 2002Bachant 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. 2002; 9: 1169-1182Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Dawlaty et al., 2008Dawlaty M.M. Malureanu L. Jeganathan K.B. Kao E. Sustmann C. Tahk S. Shuai K. Grosschedl R. van Deursen J.M. Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase IIalpha.Cell. 2008; 133: 103-115Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, Edgerton et al., 2016Edgerton H. Johansson M. Keifenheim D. Mukherjee S. Chacón J.M. Bachant J. Gardner M.K. Clarke D.J. A noncatalytic function of the topoisomerase II CTD in Aurora B recruitment to inner centromeres during mitosis.J. Cell Biol. 2016; 213: 651-664Crossref PubMed Scopus (12) Google Scholar, Ryu et al., 2010Ryu H. Furuta M. Kirkpatrick D. Gygi S.P. Azuma Y. PIASy-dependent SUMOylation regulates DNA topoisomerase IIalpha activity.J. Cell Biol. 2010; 191: 783-794Crossref PubMed Scopus (39) Google Scholar, Ryu et al., 2015aRyu H. Yoshida M.M. Sridharan V. Kumagai A. Dunphy W.G. Dasso M. Azuma Y. SUMOylation of the C-terminal domain of DNA topoisomerase IIα regulates the centromeric localization of Claspin.Cell Cycle. 2015; 14: 2777-2784Crossref PubMed Scopus (11) Google Scholar). The SUMO pathway also affects centromeric histones and other mitotic regulators (Mukhopadhyay and Dasso, 2017Mukhopadhyay D. Dasso M. The SUMO pathway in mitosis.Adv. Exp. Med. Biol. 2017; 963: 171-184Crossref PubMed Scopus (4) Google Scholar). For example, sumoylated Orc2 recruits the KDN5A demethylase to centromeres to convert H3K4me3 into H3K4me2, thus permitting non-coding RNA production from the locus and subsequent heterochromatin maintenance (Huang et al., 2016Huang C. Cheng J. Bawa-Khalfe T. Yao X. Chin Y.E. Yeh E.T.H. SUMOylated ORC2 recruits a histone demethylase to regulate centromeric histone modification and genomic stability.Cell Rep. 2016; 15: 147-157Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). In another recent example, SUMO removal was shown to help extract the Aurora B kinase from chromatin and relocate it to the spindle mid-zone, which is an essential transition during mitosis (Pelisch et al., 2014Pelisch F. Sonneville R. Pourkarimi E. Agostinho A. Blow J.J. Gartner A. Hay R.T. Dynamic SUMO modification regulates mitotic chromosome assembly and cell cycle progression in Caenorhabditis elegans.Nat. Commun. 2014; 5: 5485Crossref PubMed Google Scholar). How Aurora B is extracted is unclear but may involve the Cdc48 segregase and cofactors, which use ATP hydrolysis to remove sumoylated proteins such as the centromeric histone CENP-A from DNA (Franz et al., 2016Franz A. Ackermann L. Hoppe T. Ring of change: CDC48/p97 drives protein dynamics at chromatin.Front. Genet. 2016; 7: 73Crossref PubMed Scopus (29) Google Scholar, Mérai et al., 2014Mérai Z. Chumak N. García-Aguilar M. Hsieh T.F. Nishimura T. Schoft V.K. Bindics J. Slusarz L. Arnoux S. Opravil S. et al.The AAA-ATPase molecular chaperone Cdc48/p97 disassembles sumoylated centromeres, decondenses heterochromatin, and activates ribosomal RNA genes.Proc. Natl. Acad. Sci. USA. 2014; 111: 16166-16171Crossref PubMed Scopus (17) Google Scholar). The important SUMO-based regulatory events exemplified above could explain the drastic chromosome segregation defects arising from acute chemical inhibition of SUMO E1 or depletion of SUMO E2 and specific desumoylases (He et al., 2017He X. Riceberg J. Soucy T. Koenig E. Minissale J. Gallery M. Bernard H. Yang X. Liao H. Rabino C. et al.Probing the roles of SUMOylation in cancer cell biology by using a selective SAE inhibitor.Nat. Chem. Biol. 2017; 13: 1164-1171Crossref PubMed Scopus (34) Google Scholar, Mukhopadhyay and Dasso, 2017Mukhopadhyay D. Dasso M. The SUMO pathway in mitosis.Adv. Exp. Med. Biol. 2017; 963: 171-184Crossref PubMed Scopus (4) Google Scholar, Nacerddine et al., 2005Nacerddine K. Lehembre F. Bhaumik M. Artus J. Cohen-Tannoudji M. Babinet C. Pandolfi P.P. Dejean A. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice.Dev. Cell. 2005; 9: 769-779Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, Pelisch et al., 2014Pelisch F. Sonneville R. Pourkarimi E. Agostinho A. Blow J.J. Gartner A. Hay R.T. Dynamic SUMO modification regulates mitotic chromosome assembly and cell cycle progression in Caenorhabditis elegans.Nat. Commun. 2014; 5: 5485Crossref PubMed Google Scholar). Strikingly, aneuploidy-prone SUMO pathway mutants may produce adaptive situations wherein gaining an extra chromosome partially resets cellular homeostasis, as seen in yeast cells lacking the Ulp2 desumoylase (Ryu et al., 2016Ryu H.Y. Wilson N.R. Mehta S. Hwang S.S. Hochstrasser M. Loss of the SUMO protease Ulp2 triggers a specific multichromosome aneuploidy.Genes Dev. 2016; 30: 1881-1894Crossref PubMed Scopus (14) Google Scholar). How exactly aneuploidy can benefit cells and be maintained in this situation remains to be understood. Another future question to consider is whether centromeric regions and/or kinetochores experience SUMO-facilitated phase separation given the abundant SUMO-mediated interactions at these sites. The SUMO pathway also regulates other heterochromatic loci in addition to centromeric regions. In particular, sumoylation of the heterochromatin assembly factor HP1 promotes its association with RNA transcripts located at these regions to achieve initial HP1 targeting (Maison et al., 2011Maison C. Bailly D. Roche D. Montes de Oca R. Probst A.V. Vassias I. Dingli F. Lombard B. Loew D. Quivy J.P. Almouzni G. SUMOylation promotes de novo targeting of HP1α to pericentric heterochromatin.Nat. Genet. 2011; 43: 220-227Crossref PubMed Scopus (133) Google Scholar). Subsequent HP1 propagation along heterochromatin involves its binding to H3K9me3, catalyzed by Suv39h1 (Bannister et al., 2001Bannister A.J. Zegerman P. Partridge J.F. Miska E.A. Thomas J.O. Allshire R.C. Kouzari" @default.
• W2885330316 created "2018-08-22" @default.
• W2885330316 creator A5033457775 @default.
• W2885330316 date "2018-08-01" @default.
• W2885330316 modified "2023-10-18" @default.
• W2885330316 title "SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes" @default.
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