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 func...
| मुख्य लेखकों: | , , , , , , , |
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| स्वरूप: | Journal article |
| भाषा: | English |
| प्रकाशित: |
2010
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| _version_ | 1826271610287423488 |
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| author | D'Angiolella, V Donato, V Vijayakumar, S Saraf, A Florens, L Washburn, M Dynlacht, B Pagano, M |
| author_facet | D'Angiolella, V Donato, V Vijayakumar, S Saraf, A Florens, L Washburn, M Dynlacht, B Pagano, M |
| author_sort | D'Angiolella, V |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:59:21Z |
| format | Journal article |
| id | oxford-uuid:4e0fb4dc-a8e4-466f-a06c-6462feae228b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:59:21Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:4e0fb4dc-a8e4-466f-a06c-6462feae228b2022-03-26T15:58:56ZSCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4e0fb4dc-a8e4-466f-a06c-6462feae228bEnglishSymplectic Elements at Oxford2010D'Angiolella, VDonato, VVijayakumar, SSaraf, AFlorens, LWashburn, MDynlacht, BPagano, MGenerally, 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. |
| spellingShingle | D'Angiolella, V Donato, V Vijayakumar, S Saraf, A Florens, L Washburn, M Dynlacht, B Pagano, M SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. |
| title | SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. |
| title_full | SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. |
| title_fullStr | SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. |
| title_full_unstemmed | SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. |
| title_short | SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. |
| title_sort | scf cyclin f controls centrosome homeostasis and mitotic fidelity through cp110 degradation |
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