Review
SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

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Knocking down components of the SUMOylation machinery in eukaryotic cells causes an overall delay in cell cycle progression.

SUMO co-modifies groups of proteins throughout all phases of the cell cycle to regulate cell cycle progression.

Cyclin-dependent kinases and SUMOylation can act in concert to regulate cell cycle progression.

The dependence of cancer cells on a functioning SUMOylation system can be exploited as anticancer therapy. Inhibitors of components of the SUMOylation machinery could be used for this purpose.

Protein conjugation with Small ubiquitin-like modifier (SUMOylation) has critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancer were recently shown to be dependent on a functioning SUMOylation system, a finding that could be exploited in anticancer therapies.

Section snippets

SUMO: A Ubiquitin-like Modifier that Regulates Nuclear Processes

The complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of post-translational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications, such as phosphorylation [1], glycosylation [2], and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the

Twenty Years of SUMO Research in Cell Cycle Control

SUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO-conjugating enzyme Ubc9 was first proposed to be a ubiquitin-conjugating enzyme. Ubc9 was shown to be required for progression through mitosis by degrading M-phase cyclins [12]. Consequently, disrupting UBC9 in budding yeast resulted in large budded cells bearing only a single nucleus with a short spindle and replicated DNA, a hallmark of G2-M arrested

Redistribution of the SUMO Machinery during Mitosis

SUMO localizes at centromeres, kinetochores, and mitotic and meiotic chromosomes in different organisms, including humans and frogs 24, 25, 26. In Caenorhabditis elegans, SUMO accumulates at the metaphase plate, but its presence decreases during anaphase [27], which is regulated via the interplay between the SUMO ligase gamete-expressed 3 (GEX3)-interacting protein 17 (GEI-17) and the SUMO protease Ubiquitin-Like Protease 4 (ULP-4). These observations demonstrate that SUMO target proteins that

SUMOylation and Cyclin-Dependent Kinases in Concert

The activity and localization of the SUMO machinery can be influenced by interaction partners and by crosstalk with other post-translational modifications. Interestingly, SENP3 is heavily phosphorylated during mitosis, suggesting its regulation via mitotic kinases [42]. Additionally, kinases that are active at defined moments during cell cycle progression can also influence SUMOylation by cooperating with Ubc9. A subset of SUMO targets is regulated via an internal phosphorylation-dependent

Protein Group Modification at Mitotic Chromosomes

In many cases, several subunits of the same regulatory complexes are targeted via SUMOylation. This is consistent with proteomic studies showing that SUMO frequently modifies entire functional groups of proteins [56]. Protein group SUMOylation, potentially enhanced by the formation of longer SUMO2/3 chains on the target proteins, can trigger the formation of complexes at centromeric regions and, therefore, might be essential for chromosome alignment and segregation. Interestingly, both SENP6, a

Deregulation of the SUMO Machinery in Cancer Cells

Related to the essential role of SUMOylation in maintaining chromosome integrity and regulating cell proliferation, evidence is accumulating for a key role of SUMOylation in cancer. Many components of the SUMO machinery are highly expressed in cancer tissues, suggesting that activated SUMOylation is linked to tumor growth (Table 1). Overexpression of the SUMO-conjugating enzyme Ubc9 occurs in many types of cancer, including ovarian [63], colon, and prostate cancer [64], and promotes cell

Targeting the SUMO System

As described above, many components of the SUMO machinery are overexpressed in cancer tissues and knockdown of the SUMO pathway blocks cell proliferation and induces apoptosis. Therefore, is of interest to develop compounds that specifically block the activity of the SUMOylation machinery. Drugs targeting the SUMO-activating enzyme are currently under investigation. Chemical inhibitors, such as ginkgolic acid and anacardic acid, bind to the SUMO-activating enzyme and block the E1-SUMO

Concluding Remarks and Future Perspectives

Precisely timed post-translational modifications are essential to ensure accurate progression through the cell cycle. We now know extensive sets of ubiquitylation and phosphorylation events that are important for the transition from one cell cycle phase to the next. By contrast, we are limited in our understanding of SUMOylation events during cell cycle progression. Interestingly, inhibition of the SUMO pathway leads to cell cycle arrest in yeast and to decreased cell cycle progression and

Acknowledgments

The laboratory of A.C.O.V. is supported by the European Research Council (ERC) and the Netherlands Organisation for Scientific Research (NWO).

References (144)

  • X.D. Zhang

    SUMO-2/3 modification and binding regulate the association of CENP-E with kinetochores and progression through mitosis

    Mol. Cell

    (2008)
  • K. Romeo

    The SENP7 SUMO-protease presents a module of two HP1 interaction motifs that locks HP1 protein at pericentric heterochromatin

    Cell Rep.

    (2015)
  • R. Zunino

    Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis

    J. Biol. Chem.

    (2009)
  • Z. Guo

    Sequential posttranslational modifications program FEN1 degradation during cell-cycle progression

    Mol. Cell

    (2012)
  • I.A. Hendriks

    SUMO-2 orchestrates chromatin modifiers in response to DNA damage

    Cell Rep.

    (2015)
  • J.V. Olsen et al.

    Status of large-scale analysis of post-translational modifications by mass spectrometry

    Mol. Cell. Proteomics

    (2013)
  • F. Yang

    BubR1 is modified by sumoylation during mitotic progression

    J. Biol. Chem.

    (2012)
  • L.M. D’Ambrosio et al.

    Pds5 prevents the PolySUMO-dependent separation of sister chromatids

    Curr. Biol.

    (2014)
  • S.J. Moschos

    Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues

    Hum. Pathol.

    (2010)
  • I. Wierstra

    FOXM1 (Forkhead box M1) in tumorigenesis: overexpression in human cancer, implication in tumorigenesis, oncogenic functions, tumor-suppressive properties, and target of anticancer therapy

    Adv. Cancer Res.

    (2013)
  • J. Zhang

    Polo-like Kinase 1-mediated phosphorylation of forkhead box protein M1b antagonizes Its SUMOylation and facilitates its mitotic function

    J. Biol. Chem.

    (2015)
  • J. Zhu

    A sumoylation site in PML/RARA is essential for leukemic transformation

    Cancer Cell

    (2005)
  • S. Muller

    c-Jun and p53 activity is modulated by SUMO-1 modification

    J. Biol. Chem.

    (2000)
  • I. Fukuda

    Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate

    Chem. Biol.

    (2009)
  • G. Bossis et al.

    Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes

    Mol. Cell

    (2006)
  • G. Bossis

    The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs

    Cell Rep.

    (2014)
  • S.R. Weisshaar

    Arsenic trioxide stimulates SUMO-2/3 modification leading to RNF4-dependent proteolytic targeting of PML

    FEBS Lett.

    (2008)
  • J. Cheng

    SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia

    Cell

    (2007)
  • J. Xu

    SENP1 inhibition induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-kappaB signaling

    Biochem. Biophys. Res. Commun.

    (2015)
  • A. Kumar et al.

    Advances in the development of SUMO specific protease (SENP) inhibitors

    Comput. Struct. Biotechnol. J.

    (2015)
  • L.N. Johnson

    The regulation of protein phosphorylation

    Biochem. Soc. Trans.

    (2009)
  • K.W. Moremen

    Vertebrate protein glycosylation: diversity, synthesis and function

    Nat. Rev. Mol. Cell Biol.

    (2012)
  • C. Choudhary

    The growing landscape of lysine acetylation links metabolism and cell signalling

    Nat. Rev. Mol. Cell Biol.

    (2014)
  • G. Goldstein

    Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells

    Proc. Natl. Acad. Sci. U.S.A.

    (1975)
  • T.A. Soucy

    The NEDD8 conjugation pathway and its relevance in cancer biology and therapy

    Genes Cancer

    (2010)
  • M.S. Hipp

    FAT10, a ubiquitin-independent signal for proteasomal degradation

    Mol. Cell Biol.

    (2005)
  • M. Basler

    The ubiquitin-like modifier FAT10 in antigen processing and antimicrobial defense

    Mol. Immunol.

    (2015)
  • S. Muller

    SUMO: a regulator of gene expression and genome integrity

    Oncogene

    (2004)
  • W. Seufert

    Role of a ubiquitin-conjugating enzyme in degradation of S- and M-phase cyclins

    Nature

    (1995)
  • P. Dieckhoff

    Smt3/SUMO and Ubc9 are required for efficient APC/C-mediated proteolysis in budding yeast

    Mol. Microbiol.

    (2004)
  • E.S. Johnson

    The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer

    EMBO J.

    (1997)
  • E.S. Johnson et al.

    Cell cycle-regulated attachment of the ubiquitin-related protein SUMO to the yeast septins

    J. Cell Biol.

    (1999)
  • L. Wang

    SUMO2 is essential while SUMO3 is dispensable for mouse embryonic development

    EMBO Rep.

    (2014)
  • E. Evdokimov

    Loss of SUMO1 in mice affects RanGAP1 localization and formation of PML nuclear bodies, but is not lethal as it can be compensated by SUMO2 or SUMO3

    J. Cell Sci.

    (2008)
  • F.P. Zhang

    Sumo-1 function is dispensable in normal mouse development

    Mol. Cell. Biol.

    (2008)
  • H. Neyret-Kahn

    Sumoylation at chromatin governs coordinated repression of a transcriptional program essential for cell growth and proliferation

    Genome Res.

    (2013)
  • F. Ayaydin et al.

    Distinct in vivo dynamics of vertebrate SUMO paralogues

    Mol. Biol. Cell

    (2004)
  • P.W. Brown

    Small ubiquitin-related modifier (SUMO)-1, SUMO-2/3 and SUMOylation are involved with centromeric heterochromatin of chromosomes 9 and 1 and proteins of the synaptonemal complex during meiosis in men

    Hum. Reprod.

    (2008)
  • M. Vigodner

    Sumoylation precedes accumulation of phosphorylated H2AX on sex chromosomes during their meiotic inactivation

    Chromosome Res.

    (2009)
  • F. Pelisch

    Dynamic SUMO modification regulates mitotic chromosome assembly and cell cycle progression in Caenorhabditis elegans

    Nat. Commun.

    (2014)
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