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SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation.

Generally, F-box proteins are the substrate recognition subunits of SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complexes, which mediate the timely proteolysis of important eukaryotic regulatory proteins. Mammalian genomes encode roughly 70 F-box proteins, but only a handful have established functions. The F-box protein family obtained its name from Cyclin F (also called Fbxo1), in which the F-box motif (the approximately 40-amino-acid domain required for binding to Skp1) was first described. Cyclin F, which is encoded by an essential gene, also contains a cyclin box domain, but in contrast to most cyclins, it does not bind or activate any cyclin-dependent kinases (CDKs). However, like other cyclins, Cyclin F oscillates during the cell cycle, with protein levels peaking in G2. Despite its essential nature and status as the founding member of the F-box protein family, Cyclin F remains an orphan protein, whose functions are unknown. Starting from an unbiased screen, we identified CP110, a protein that is essential for centrosome duplication, as an interactor and substrate of Cyclin F. Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation. siRNA-mediated depletion of Cyclin F in G2 induces centrosomal and mitotic abnormalities, such as multipolar spindles and asymmetric, bipolar spindles with lagging chromosomes. These phenotypes were reverted by co-silencing CP110 and were recapitulated by expressing a stable mutant of CP110 that cannot bind Cyclin F. Finally, expression of a stable CP110 mutant in cultured cells also promotes the formation of micronuclei, a hallmark of chromosome instability. We propose that SCF(Cyclin F)-mediated degradation of CP110 is required for the fidelity of mitosis and genome integrity.

Pubmed ID: 20596027

Authors

  • D'Angiolella V
  • Donato V
  • Vijayakumar S
  • Saraf A
  • Florens L
  • Washburn MP
  • Dynlacht B
  • Pagano M

Journal

Nature

Publication Data

July 1, 2010

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01 GM057587
  • Agency: NIGMS NIH HHS, Id: R01 GM057587-12
  • Agency: NIGMS NIH HHS, Id: R01-GM057587
  • Agency: NIA NIH HHS, Id: R21 AG032560
  • Agency: NIA NIH HHS, Id: R21 AG032560-02
  • Agency: NIA NIH HHS, Id: R21-AG032560
  • Agency: NCI NIH HHS, Id: R37 CA076584
  • Agency: NCI NIH HHS, Id: R37 CA076584-12
  • Agency: NCI NIH HHS, Id: R37-CA076584
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Cell Cycle Proteins
  • Cell Line
  • Cell Line, Tumor
  • Centrioles
  • Centrosome
  • Cyclins
  • G2 Phase
  • Homeostasis
  • Humans
  • Mice
  • Microtubule-Associated Proteins
  • Mitosis
  • Multiprotein Complexes
  • Phenotype
  • Phosphoproteins
  • Protein Binding
  • SKP Cullin F-Box Protein Ligases
  • Substrate Specificity
  • Ubiquitination