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Cited by 248Microtubule and mitosis dynamicsUbiquitin and proteasome pathwaysCancer-related Molecular Pathways

UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit

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Garnett, Mathew J., Mansfeld, Jörg, Godwin, Colin, Matsusaka, Takahiro, Wu, Jiahua, Russell, Paul, Pines, Jonathon, Venkitaraman, Ashok R.·2009·Nature Cell Biology
DOI 10.1038/ncb1983PMC PMC2875106
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Abstract

The anaphase-promoting complex (APC/C), a ubiquitin ligase, is the target of the spindle-assembly checkpoint (SAC), and it ubiquitylates protein substrates whose degradation regulates progress through mitosis. The identity of the ubiquitin-conjugating (E2) enzymes that work with the APC/C is unclear. In an RNA interference (RNAi) screen for factors that modify release from drug-induced SAC activation, we identified the E2 enzyme UBE2S as an APC/C auxiliary factor that promotes mitotic exit. UBE2S is dispensable in a normal mitosis, but its depletion prolongs drug-induced mitotic arrest and suppresses mitotic slippage. In vitro, UBE2S elongates ubiquitin chains initiated by the E2 enzymes UBCH10 and UBCH5, enhancing the degradation of APC/C substrates by the proteasome. Indeed, following release from SAC-induced mitotic arrest, UBE2S-depleted cells neither degrade crucial APC/C substrates, nor silence this checkpoint, whereas bypassing the SAC through BUBR1 depletion or Aurora-B inhibition negates the requirement for UBE2S. Thus, UBE2S functions with the APC/C in a two-step mechanism to control substrate ubiquitylation that is essential for mitotic exit after prolonged SAC activation, providing a new model for APC/C function in human cells.

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  • The APC complex concomitantly recruits the E2 ligases UbcH10 and Ube2S, and both are necessary for Lys-11-linked polyubiquitination of mitotic targets.

    “The APC complex, for instance, concomitantly recruits the E2 ligases UbcH10 and Ube2S, and both are necessary for Lys-11-linked polyubiquitination of mitotic targets (29).”

    From Distinct Functional Domains Contribute to Degradation of the Low Density Lipoprotein Receptor (LDLR) by the E3 Ubiquitin Ligase Inducible Degrader of the LDLR (IDOL) (2011) · cites this paper as [29]

    The paper’s in vitro APC/C assays (Figure 4a–c; page unavailable) show that UBE2S extends ubiquitin chains initiated by UBCH10, supporting cooperation between the enzymes. They also show that UBCH5 can substitute for UBCH10. The paper does not establish concomitant recruitment—it raises competition for APC/C binding as a possibility—or identify the resulting chains as Lys-11-linked, so the claim that both named enzymes are necessary for those chains is not supported. (LLM, conf=0.88)

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Research works printed but not linked: 32

  1. [1]Musacchio A Salmon ED The spindle-assembly checkpoint in space and time Nat Rev Mol Cell Biol 2007 8 379 393 17426725
  2. [2]Kim SH Lin DP Matsumoto S Kitazono A Matsumoto T Fission yeast Slp1: an effector of the Mad2-dependent spindle checkpoint Science 1998 279 1045 1047 9461438
  3. [3]Nilsson J Yekezare M Minshull J Pines J The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction Nat Cell Biol 2008 10 1411 1420 18997788 PMC2635557
  4. [4]Pines J Mitosis: a matter of getting rid of the right protein at the right time Trends Cell Biol 2006 16 55 63 16337124
  5. [5]Peters JM The anaphase promoting complex/cyclosome: a machine designed to destroy Nat Rev Mol Cell Biol 2006 7 644 656 16896351
  6. [6]Tang Z APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex Mol Biol Cell 2001 12 3839 3851 11739784 PMC60759
  7. [7]Aristarkhov A E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins Proc Natl Acad Sci U S A 1996 93 4294 4299 8633058 PMC39529
  8. [8]Yu H King RW Peters JM Kirschner MW Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation Curr Biol 1996 6 455 466 8723350
  9. [9]Seino H Kishi T Nishitani H Yamao F Two ubiquitin-conjugating enzymes, UbcP1/Ubc4 and UbcP4/Ubc11, have distinct functions for ubiquitination of mitotic cyclin Mol Cell Biol 2003 23 3497 3505 12724408 PMC164763
  10. [10]Osaka F Seino H Seno T Yamao F A ubiquitin-conjugating enzyme in fission yeast that is essential for the onset of anaphase in mitosis Mol Cell Biol 1997 17 3388 3397 9154838 PMC232192
  11. [11]Rodrigo-Brenni MC Morgan DO Sequential E2s drive polyubiquitin chain assembly on APC targets Cell 2007 130 127 139 17632060
  12. [12]Mathe E The E2-C vihar is required for the correct spatiotemporal proteolysis of cyclin B and itself undergoes cyclical degradation Curr Biol 2004 14 1723 1733 15458643
  13. [13]Walker A Acquaviva C Matsusaka T Koop L Pines J UbcH10 has a rate-limiting role in G1 phase but might not act in the spindle checkpoint or as part of an autonomous oscillator J Cell Sci 2008 121 2319 2326 18559889
  14. [14]Rape M Kirschner MW Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry Nature 2004 432 588 595 15558010
  15. [15]Thrower JS Hoffman L Rechsteiner M Pickart CM Recognition of the polyubiquitin proteolytic signal EMBO J 2000 19 94 102 10619848 PMC1171781
  16. [16]Rieder CL Maiato H Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint Dev Cell 2004 7 637 651 15525526
  17. [17]Gascoigne KE Taylor SS Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs Cancer Cell 2008 14 111 122 18656424
  18. [18]Brito DA Rieder CL Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint Curr Biol 2006 16 1194 1200 16782009 PMC2749311
  19. [19]Kapoor TM Mayer TU Coughlin ML Mitchison TJ Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5 J Cell Biol 2000 150 975 988 10973989 PMC2175262
  20. [20]Mayer TU Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen Science 1999 286 971 974 10542155
  21. [21]DeBonis S In vitro screening for inhibitors of the human mitotic kinesin Eg5 with antimitotic and antitumor activities Mol Cancer Ther 2004 3 1079 1090 15367702
  22. [22]Gartner M Development and biological evaluation of potent and specific inhibitors of mitotic Kinesin Eg5 Chembiochem 2005 6 1173 1177 15912555
  23. [23]den Elzen N Pines J Cyclin A is destroyed in prometaphase and can delay chromosome alignment and anaphase J Cell Biol 2001 153 121 136 11285279 PMC2185531
  24. [24]Hames RS Wattam SL Yamano H Bacchieri R Fry AM APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box EMBO J 2001 20 7117 7127 11742988 PMC125337
  25. [25]Brito DA Yang Z Rieder CL Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied J Cell Biol 2008 182 623 629 18710927 PMC2518701
  26. [26]Choi E BubR1 acetylation at prometaphase is required for modulating APC/C activity and timing of mitosis EMBO J 2009 PMC2684026 19407811
  27. [27]Herzog F Structure of the anaphase-promoting complex/cyclosome interacting with a mitotic checkpoint complex Science 2009 323 1477 1481 19286556 PMC2989460
  28. [28]Ditchfield C Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores J Cell Biol 2003 161 267 280 12719470 PMC2172902
  29. [29]Bassermann F The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint Cell 2008 134 256 267 18662541 PMC2591934
  30. [30]Stegmeier F Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities Nature 2007 446 876 881 17443180
  31. [31]Song L Rape M Reverse the curse--the role of deubiquitination in cell cycle control Curr Opin Cell Biol 2008 20 156 163 18346885 PMC2387050
  32. [32]Hagting A Karlsson C Clute P Jackman M Pines J MPF localization is controlled by nuclear export EMBO J 1998 17 4127 4138 9670027 PMC1170745

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Authors
Garnett, M. J., Mansfeld, J., Godwin, C., Matsusaka, T., Wu, J., Russell, P., Pines, J., & Venkitaraman, A. R.
Affiliations
  • University of Cambridge (GB)
  • The Gurdon Institute (GB)
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2009-10-11
Volume
11
Issue
11
Pages
1363-1369
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/ncb1983
PMC
PMC2875106
OpenAlex
W2013098933
Cited by
248
References
0
Citations by year
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FWCI
9.40
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Wellcome Trust
  • Cancer Research UK
  • Canadian Institutes of Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
UBE2S, anaphase-promoting complex, ubiquitin chain elongation, E2 ubiquitin-conjugating enzyme, spindle assembly checkpoint, mitotic exit, mitotic slippage, proteasomal degradation, UbcH10, BubR1, Aurora B kinase, mitotic arrest
MeSH terms
HeLa Cells, Humans, Mitosis, Substrate Specificity, RNA Interference, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Conjugating Enzymes, Anaphase-Promoting Complex-Cyclosome

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