The PIDDosome activates p53 in response to supernumerary centrosomes.

Luca L Fava,Andreas Villunger,Erich A Nigg,Claudia Soratroi,Manuel D Haschka,Stephan Geley,Valentina Sladky,Lisa Eiterer,Fabian Schuler,Guenter Weiss,Egon Demetz

doi:10.1101/gad.289728.116

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.

Highlights

Chromosome segregation errors pose a substantial danger to individual cells and multicellular organisms as a whole
Our analyses demonstrate that Caspase-2 becomes selectively activated upon cytokinesis failure in a PIDDosome-dependent manner, resulting in MDM2 cleavage, p53 activation, and p21-dependent cell cycle arrest
CRISPR–Cas9-mediated deletion of Caspase-2, PIDD1, or RAIDD led to indistinguishable phenotypes (Fig. 2A,B), demonstrating that following cytokinesis failure, the PIDDosome acts as a functional unit to activate p53

Summary

Introduction

Chromosome segregation errors pose a substantial danger to individual cells and multicellular organisms as a whole. While genetically programmed cytokinesis abrogation can be an integral part of the development of certain mammalian cell types such as hepatocytes or cardiomyocytes during organogenesis (Pandit et al 2013), unscheduled cytokinesis failure has been shown to be oncogenic in animal models (Fujiwara et al 2005) The latter findings go well with the high frequency of whole-genome duplication (WGD) events observed in the course of carcinogenesis in humans. Caspase-2 classifies as an initiator caspase suggesting an apical position in signaling Members of this class, such as Caspase-9, Caspase-8, and Caspase-1, are usually activated in highmolecular-weight signaling platforms, such as the apoptosome, the death-inducing signaling complex (DISC), or the inflammasome, and each of these assemble in response to defined cues. The specific cue activating the PIDDosome remained undefined and led to numerous hypotheses about its function (Bock et al 2012; Fava et al 2012)

Objectives

Methods

Results

Conclusion