Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities

Frank Stegmeier, Michael Rape, Viji M. Draviam, Grzegorz Nalepa, Mathew E. Sowa, Xiaolu L. Ang, E. Robert McDonald, Mamie Z. Li, Gregory J. Hannon, Peter K. Sorger, Marc W. Kirschner, J. Wade Harper, Stephen J. Elledge

Research output: Contribution to journalArticle

268 Citations (Scopus)

Abstract

The spindle checkpoint prevents chromosome mis-segregation by delaying sister chromatid separation until all chromosomes have achieved bipolar attachment to the mitotic spindle. Its operation is essential for accurate chromosome segregation, whereas its dysregulation can contribute to birth defects and tumorigenesis. The target of the spindle checkpoint is the anaphase-promoting complex (APC), a ubiquitin ligase that promotes sister chromatid separation and progression to anaphase. Using a short hairpin RNA screen targeting components of the ubiquitin-proteasome pathway in human cells, we identified the deubiquitinating enzyme USP44 (ubiquitin-specific protease 44) as a critical regulator of the spindle checkpoint. USP44 is not required for the initial recognition of unattached kinetochores and the subsequent recruitment of checkpoint components. Instead, it prevents the premature activation of the APC by stabilizing the APC-inhibitory Mad2-Cdc20 complex. USP44 deubiquitinates the APC coactivator Cdc20 both in vitro and in vivo, and thereby directly counteracts the APC-driven disassembly of Mad2-Cdc20 complexes (discussed in an accompanying paper). Our findings suggest that a dynamic balance of ubiquitination by the APC and deubiquitination by USP44 contributes to the generation of the switch-like transition controlling anaphase entry, analogous to the way that phosphorylation and dephosphorylation of Cdk1 by Wee1 and Cdc25 controls entry into mitosis.

Original languageEnglish (US)
Pages (from-to)876-881
Number of pages6
JournalNature
Volume446
Issue number7138
DOIs
StatePublished - Apr 19 2007
Externally publishedYes

Fingerprint

Anaphase-Promoting Complex-Cyclosome
Anaphase
Ubiquitination
Ubiquitin-Specific Proteases
Chromosome Segregation
Chromatids
Ubiquitin
Kinetochores
Spindle Apparatus
Proteasome Endopeptidase Complex
Ligases
Mitosis
Small Interfering RNA
Carcinogenesis
Chromosomes
Phosphorylation

ASJC Scopus subject areas

  • General

Cite this

Stegmeier, F., Rape, M., Draviam, V. M., Nalepa, G., Sowa, M. E., Ang, X. L., ... Elledge, S. J. (2007). Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. Nature, 446(7138), 876-881. https://doi.org/10.1038/nature05694

Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. / Stegmeier, Frank; Rape, Michael; Draviam, Viji M.; Nalepa, Grzegorz; Sowa, Mathew E.; Ang, Xiaolu L.; McDonald, E. Robert; Li, Mamie Z.; Hannon, Gregory J.; Sorger, Peter K.; Kirschner, Marc W.; Harper, J. Wade; Elledge, Stephen J.

In: Nature, Vol. 446, No. 7138, 19.04.2007, p. 876-881.

Research output: Contribution to journalArticle

Stegmeier, F, Rape, M, Draviam, VM, Nalepa, G, Sowa, ME, Ang, XL, McDonald, ER, Li, MZ, Hannon, GJ, Sorger, PK, Kirschner, MW, Harper, JW & Elledge, SJ 2007, 'Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities', Nature, vol. 446, no. 7138, pp. 876-881. https://doi.org/10.1038/nature05694
Stegmeier F, Rape M, Draviam VM, Nalepa G, Sowa ME, Ang XL et al. Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. Nature. 2007 Apr 19;446(7138):876-881. https://doi.org/10.1038/nature05694
Stegmeier, Frank ; Rape, Michael ; Draviam, Viji M. ; Nalepa, Grzegorz ; Sowa, Mathew E. ; Ang, Xiaolu L. ; McDonald, E. Robert ; Li, Mamie Z. ; Hannon, Gregory J. ; Sorger, Peter K. ; Kirschner, Marc W. ; Harper, J. Wade ; Elledge, Stephen J. / Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. In: Nature. 2007 ; Vol. 446, No. 7138. pp. 876-881.
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