The PIDDosome activates p53 in response to supernumerary centrosomes
- Luca L. Fava1,
- Fabian Schuler1,6,
- Valentina Sladky1,6,
- Manuel D. Haschka1,6,
- Claudia Soratroi1,
- Lisa Eiterer1,
- Egon Demetz2,
- Guenter Weiss2,
- Stephan Geley3,
- Erich A. Nigg4 and
- Andreas Villunger1,5
- 1Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria;
- 2Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020 Innsbruck, Austria;
- 3Division of Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria;
- 4Biozentrum, University of Basel, 4056 Basel, Switzerland;
- 5Tyrolean Cancer Research Institute, 6020 Innsbruck, Austria
- Corresponding authors: luca.fava{at}i-med.ac.at, andreas.villunger{at}i-med.ac.at
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↵6 These authors contributed equally to this work.
Abstract
Centrosomes, the main microtubule-organizing centers in animal cells, are replicated exactly once during the cell division cycle to form the poles of the mitotic spindle. Supernumerary centrosomes can lead to aberrant cell division and have been causally linked to chromosomal instability and cancer. Here, we report that an increase in the number of mature centrosomes, generated by disrupting cytokinesis or forcing centrosome overduplication, triggers the activation of the PIDDosome multiprotein complex, leading to Caspase-2-mediated MDM2 cleavage, p53 stabilization, and p21-dependent cell cycle arrest. This pathway also restrains the extent of developmentally scheduled polyploidization by regulating p53 levels in hepatocytes during liver organogenesis. Taken together, the PIDDosome acts as a first barrier, engaging p53 to halt the proliferation of cells carrying more than one mature centrosome to maintain genome integrity.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.289728.116.
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Freely available online through the Genes & Development Open Access option.
- Received August 24, 2016.
- Accepted December 15, 2016.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.