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

Journal article

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.

Authors: D'Angiolella, V; Donato, V; Vijayakumar, S; Saraf, A; Florens, L

• Publication status: Published
• Journal: Nature
• Volume: 466
• Issue: 7302
• Pages: 138-142
• Publication date: 2010-07-01
• DOI: 10.1038/nature09140
• EISSN: 1476-4687
• ISSN: 0028-0836
• Language: English
• Keywords: Microtubule-Associated Proteins; Cyclins; Protein Binding; Animals; SKP Cullin F-Box Protein Ligases; Mitosis; Cell Cycle Proteins; Phenotype; Ubiquitination; Humans; Cell Line, Tumor; Substrate Specificity; Homeostasis; Phosphoproteins; Multiprotein Complexes; Centrosome; Cell Line; Mice; Centrioles; G2 Phase