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Opposing post-translational modifications regulate Cep76 function to suppress centriole amplification

Oncogene volume 35, pages 5377–5387 (2016)Cite this article

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Abstract

Centrioles are critical for many cellular processes including cell division and cilia assembly. The number of centrioles within a cell is under strict control, and deregulation of centriole copy number is a hallmark of cancer. The molecular mechanisms that halt centriole amplification have not been fully elucidated. Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. A novel Cep76 mutation S83C identified in a cancer patient fails to prevent centriole amplification. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. Cep76 can also be acetylated, and enforced acetylation at K279 dampens the protein’s ability to inhibit amplification and precludes S83 phosphorylation. Acetylation of Cep76 normally occurs in G2 phase and correlates with loss of protein function. Our data suggest that temporal changes in post-translational modifications of Cep76 during the cell cycle regulate its capacity to suppress centriole amplification, and its deregulation may contribute to malignancy.

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Acknowledgements

We thank all members of the Tsang laboratory for constructive advice, E Gomes and J Song for assistance with cloning, and Ross Tomaino and Denis Faubert for assistance with mass spectrometry. WYT is a Canadian Institutes of Health Research New Investigator and a Fonds de recherche Santé Junior 1 Research Scholar. This work was supported by the Canadian Institutes of Health Research (MOP-115033 to WYT) and the Natural Sciences and Engineering Research Council of Canada.

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Authors and Affiliations

  1. Cell Division and Centrosome Biology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada

    M Barbelanne, A Chiu, J Qian & W Y Tsang

  2. Département de pathologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada

    M Barbelanne & W Y Tsang

  3. Division of Experimental Medicine, McGill University, Montréal, Québec, Canada

    W Y Tsang

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  1. M Barbelanne
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Correspondence to W Y Tsang.

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Barbelanne, M., Chiu, A., Qian, J. et al. Opposing post-translational modifications regulate Cep76 function to suppress centriole amplification. Oncogene 35, 5377–5387 (2016). https://doi.org/10.1038/onc.2016.74

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