Abstract
Deregulated centrosome duplication can result in genetic instability and contribute to tumorigenesis1,2. Here, we show that centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 (ref. 3) as its targeting subunit. Depletion of endogenous FBXW5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles. We identify the centriolar protein HsSAS-6 (refs 4, 5) as a critical substrate of the SCF–FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. The activity of SCF–FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6. FBXW5 is a cell-cycle-regulated protein with expression levels peaking at the G1/S transition. We show that FBXW5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery. In summary, we show that a cell-cycle-regulated SCF complex is regulated by the kinase PLK4, and that this in turn restricts centrosome re-duplication through degradation of the centriolar protein HsSAS-6.
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Change history
06 July 2011
In the version of this article initially published online, all proteins should have been upper case. This has been corrected in both the HTML and PDF versions of the article.
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Acknowledgements
We thank H. S. Malek, J. Roberts and A. Besson for critical reading of the manuscript. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Transregio 77) to N.P.M., and by a grant from the Deutsche Krebshilfe to V.G. and S.K., as well as by the Swiss Cancer League to P.G. (OCS KLS 02024-02-2007).
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A.P., Y.H., D.K., M.M., S.C., U.K. and A.P. carried out experiments, analysed data and designed figures; V.G., S.K., A.P., M.P.M., I.H., P.G. and N.P.M. designed experiments, analysed data, designed figures and wrote the manuscript.
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Puklowski, A., Homsi, Y., Keller, D. et al. The SCF–FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication. Nat Cell Biol 13, 1004–1009 (2011). https://doi.org/10.1038/ncb2282
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DOI: https://doi.org/10.1038/ncb2282
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