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Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities.

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.

Pubmed ID: 17443180

Authors

  • 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

Journal

Nature

Publication Data

April 19, 2007

Associated Grants

  • Agency: NINDS NIH HHS, Id: F31 NS054507-01
  • Agency: NIA NIH HHS, Id: R01 AG011085

Mesh Terms

  • Anaphase
  • Anaphase-Promoting Complex-Cyclosome
  • Calcium-Binding Proteins
  • Cdc20 Proteins
  • Cell Cycle Proteins
  • Endopeptidases
  • HeLa Cells
  • Humans
  • Kinetochores
  • Mad2 Proteins
  • Paclitaxel
  • Repressor Proteins
  • Reproducibility of Results
  • Ubiquitin
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligase Complexes
  • Ubiquitin-Specific Proteases