Home LiteratureArticle Details
PMID: 17762865 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

SUMO-targeted ubiquitin ligases in genome stability.

The EMBO journal ·Vol. 26 ·No. 18 ·2007-09-19 ·Pages 4089-101

Prudden J, Pebernard S, Raffa G, Slavin DA, Perry JJ, Tainer JA, McGowan CH, Boddy MN

Abstract

We identify the SUMO-Targeted Ubiquitin Ligase (STUbL) family of proteins and propose that STUbLs selectively ubiquitinate sumoylated proteins and proteins that contain SUMO-like domains (SLDs). STUbL recruitment to sumoylated/SLD proteins is mediated by tandem SUMO interaction motifs (SIMs) within the STUbLs N-terminus. STUbL-mediated ubiquitination maintains sumoylation pathway homeostasis by promoting target protein desumoylation and/or degradation. Thus, STUbLs establish a novel mode of communication between the sumoylation and ubiquitination pathways. STUbLs are evolutionarily conserved and include: Schizosaccharomyces pombe Slx8-Rfp (founding member), Homo sapiens RNF4, Dictyostelium discoideum MIP1 and Saccharomyces cerevisiae Slx5-Slx8. Cells lacking Slx8-Rfp accumulate sumoylated proteins, display genomic instability, and are hypersensitive to genotoxic stress. These phenotypes are suppressed by deletion of the major SUMO ligase Pli1, demonstrating the specificity of STUbLs as regulators of sumoylated proteins. Notably, human RNF4 expression restores SUMO pathway homeostasis in fission yeast lacking Slx8-Rfp, underscoring the evolutionary functional conservation of STUbLs. The DNA repair factor Rad60 and its human homolog NIP45, which contain SLDs, are candidate STUbL targets. Consistently, Rad60 and Slx8-Rfp mutants have similar DNA repair defects.

MeSH Terms
Adaptation, Physiological/drug effects Amino Acid Motifs Amino Acid Sequence Conserved Sequence DNA Damage DNA Repair/drug effects DNA Replication/drug effects Evolution, Molecular Gene Deletion Genomic Instability/drug effects Homeostasis/drug effects Humans Microbial Viability/drug effects Models, Biological Molecular Sequence Data Mutagens/pharmacology Phenotype Protein Binding/drug effects Saccharomyces cerevisiae/cytology,drug effects,enzymology Schizosaccharomyces/drug effects,enzymology,genetics Schizosaccharomyces pombe Proteins/chemistry Sequence Homology, Amino Acid Small Ubiquitin-Related Modifier Proteins/metabolism Ubiquitin-Conjugating Enzymes/metabolism
Chemicals
Mutagens Schizosaccharomyces pombe Proteins Small Ubiquitin-Related Modifier Proteins Ubiquitin-Conjugating Enzymes
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Prudden John
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Pebernard Stephanie
Raffa Grazia
Slavin Daniela A
Perry J Jefferson P
Tainer John A
McGowan Clare H
Boddy Michael N
References (49)
49 references, click to expand
  1. Cell-cycle-dependent localisation of Ulp1, a Schizosaccharomyces pombe Pmt3 (SUMO)-specific protease.
    J Cell Sci. 2002 Mar 15;115(Pt 6):1113-22 PMID: 11884512
  2. An E3-like factor that promotes SUMO conjugation to the yeast septins.
    Cell. 2001 Sep 21;106(6):735-44 PMID: 11572779
  3. Mus81-Eme1 and Rqh1 involvement in processing stalled and collapsed replication forks.
    J Biol Chem. 2002 Sep 6;277(36):32753-9 PMID: 12084712
  4. The inhibitory function in human progesterone receptor N termini binds SUMO-1 protein to regulate autoinhibition and transrepression.
    J Biol Chem. 2002 Sep 13;277(37):33950-6 PMID: 12114521
  5. Small ubiquitin-related modifier-1 (SUMO-1) modification of the glucocorticoid receptor.
    Biochem J. 2002 Nov 1;367(Pt 3):907-11 PMID: 12144530
  6. Replication checkpoint kinase Cds1 regulates recombinational repair protein Rad60.
    Mol Cell Biol. 2003 Aug;23(16):5939-46 PMID: 12897162
  7. Histone sumoylation is associated with transcriptional repression.
    Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13225-30 PMID: 14578449
  8. Down-regulation of estrogen receptor beta and transcriptional coregulator SNURF/RNF4 in testicular germ cell cancer.
    Eur Urol. 2003 Dec;44(6):742-7; discussion 747 PMID: 14644130
  9. Assigning function to yeast proteins by integration of technologies.
    Mol Cell. 2003 Dec;12(6):1353-65 PMID: 14690591
  10. Transcriptional coregulator SNURF (RNF4) possesses ubiquitin E3 ligase activity.
    FEBS Lett. 2004 Feb 27;560(1-3):56-62 PMID: 14987998
  11. SUMO and ubiquitin in the nucleus: different functions, similar mechanisms?
    Genes Dev. 2004 Sep 1;18(17):2046-59 PMID: 15342487
  12. Role of the fission yeast SUMO E3 ligase Pli1p in centromere and telomere maintenance.
    EMBO J. 2004 Oct 1;23(19):3844-53 PMID: 15359282
  13. Global analysis of protein sumoylation in Saccharomyces cerevisiae.
    J Biol Chem. 2004 Oct 29;279(44):45662-8 PMID: 15326169
  14. Thiamine-repressible expression vectors pREP and pRIP for fission yeast.
    Gene. 1993 Jan 15;123(1):127-30 PMID: 8422996
  15. The Schizosaccharomyces pombe hus5 gene encodes a ubiquitin conjugating enzyme required for normal mitosis.
    J Cell Sci. 1995 Feb;108 ( Pt 2):475-86 PMID: 7768995
  16. Replication checkpoint enforced by kinases Cds1 and Chk1.
    Science. 1998 May 8;280(5365):909-12 PMID: 9572736
  17. Identification of a novel RING finger protein as a coregulator in steroid receptor-mediated gene transcription.
    Mol Cell Biol. 1998 Sep;18(9):5128-39 PMID: 9710597
  18. Nse2, a component of the Smc5-6 complex, is a SUMO ligase required for the response to DNA damage.
    Mol Cell Biol. 2005 Jan;25(1):185-96 PMID: 15601841
  19. Defining the SUMO-modified proteome by multiple approaches in Saccharomyces cerevisiae.
    J Biol Chem. 2005 Feb 11;280(6):4102-10 PMID: 15590687
  20. SUMO-1 promotes association of SNURF (RNF4) with PML nuclear bodies.
    Exp Cell Res. 2005 Mar 10;304(1):224-33 PMID: 15707587
  21. Proteins with two SUMO-like domains in chromatin-associated complexes: the RENi (Rad60-Esc2-NIP45) family.
    BMC Bioinformatics. 2005;6:22 PMID: 15698469
  22. Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification.
    Hum Mol Genet. 2005 May 15;14(10):1351-65 PMID: 15829507
  23. SUMO modification is involved in the maintenance of heterochromatin stability in fission yeast.
    Mol Cell. 2005 Sep 16;19(6):817-28 PMID: 16168376
  24. Mutual interactions between the SUMO and ubiquitin systems: a plea of no contest.
    Trends Cell Biol. 2005 Oct;15(10):525-32 PMID: 16125934
  25. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice.
    Dev Cell. 2005 Dec;9(6):769-79 PMID: 16326389
  26. Rhp51-dependent recombination intermediates that do not generate checkpoint signal are accumulated in Schizosaccharomyces pombe rad60 and smc5/6 mutants after release from replication arrest.
    Mol Cell Biol. 2006 Jan;26(1):343-53 PMID: 16354704
  27. RNF4 is a growth inhibitor expressed in germ cells but not in human testicular tumors.
    Am J Pathol. 2001 Oct;159(4):1225-30 PMID: 11583949
  28. SP-RING for SUMO: new functions bloom for a ubiquitin-like protein.
    Cell. 2001 Oct 5;107(1):5-8 PMID: 11595179
  29. Mus81-Eme1 are essential components of a Holliday junction resolvase.
    Cell. 2001 Nov 16;107(4):537-48 PMID: 11719193
  30. Systematic genetic analysis with ordered arrays of yeast deletion mutants.
    Science. 2001 Dec 14;294(5550):2364-8 PMID: 11743205
  31. The Nse5-Nse6 dimer mediates DNA repair roles of the Smc5-Smc6 complex.
    Mol Cell Biol. 2006 Mar;26(5):1617-30 PMID: 16478984
  32. Suppression of genomic instability by SLX5 and SLX8 in Saccharomyces cerevisiae.
    DNA Repair (Amst). 2006 Mar 7;5(3):336-46 PMID: 16325482
  33. Genetic analysis connects SLX5 and SLX8 to the SUMO pathway in Saccharomyces cerevisiae.
    Genetics. 2006 Mar;172(3):1499-509 PMID: 16387868
  34. Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications.
    Genes Dev. 2006 Apr 15;20(8):966-76 PMID: 16598039
  35. Regulation of DNA repair by ubiquitylation.
    Nat Rev Mol Cell Biol. 2006 May;7(5):323-34 PMID: 16633336
  36. Specification of SUMO1- and SUMO2-interacting motifs.
    J Biol Chem. 2006 Jun 9;281(23):16117-27 PMID: 16524884
  37. SUMO-binding motifs mediate the Rad60-dependent response to replicative stress and self-association.
    J Biol Chem. 2006 Sep 22;281(38):27973-81 PMID: 16880212
  38. Modification of proteins by ubiquitin and ubiquitin-like proteins.
    Annu Rev Cell Dev Biol. 2006;22:159-80 PMID: 16753028
  39. Control of Rad52 recombination activity by double-strand break-induced SUMO modification.
    Nat Cell Biol. 2006 Nov;8(11):1284-90 PMID: 17013376
  40. Ubc9- and mms21-mediated sumoylation counteracts recombinogenic events at damaged replication forks.
    Cell. 2006 Nov 3;127(3):509-22 PMID: 17081974
  41. SUMO modification of Rad22, the Schizosaccharomyces pombe homologue of the recombination protein Rad52.
    Nucleic Acids Res. 2001 Oct 15;29(20):4179-86 PMID: 11600706
  42. 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 Dec;19(12):8660-72 PMID: 10567589
  43. Coregulator small nuclear RING finger protein (SNURF) enhances Sp1- and steroid receptor-mediated transcription by different mechanisms.
    J Biol Chem. 2000 Jan 7;275(1):571-9 PMID: 10617653
  44. Covalent modification of the Werner's syndrome gene product with the ubiquitin-related protein, SUMO-1.
    J Biol Chem. 2000 Jul 14;275(28):20963-6 PMID: 10806190
  45. RING finger proteins: mediators of ubiquitin ligase activity.
    Cell. 2000 Sep 1;102(5):549-52 PMID: 11007473
  46. Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1.
    Mol Cell Biol. 2000 Dec;20(23):8758-66 PMID: 11073977
  47. Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1).
    Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14145-50 PMID: 11121022
  48. Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae.
    Genetics. 2001 Jan;157(1):103-18 PMID: 11139495
  49. Regulated SUMOylation and ubiquitination of DdMEK1 is required for proper chemotaxis.
    Dev Cell. 2002 Jun;2(6):745-56 PMID: 12062087
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7601838
Published
2007-09-19
Epub
2007-00-30
Pages
4089-101
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2230673
Subset
IM
Grants
NCI NIH HHS · R01 CA095114 · United States
NIGMS NIH HHS · R01 GM068608 · United States
NCI NIH HHS · CA095114 · United States
NIGMS NIH HHS · GM068608 · United States
External Links
PubMed source DOI: 10.1038/sj.emboj.7601838 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2