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  • Original Paper
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Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy

Abstract

A conflict in cell cycle progression or DNA damage can lead to mitotic catastrophe when the DNA structure checkpoints are inactivated, for instance when the checkpoint kinase Chk2 is inhibited. Here we show that in such conditions, cells die during the metaphase of the cell cycle, as a result of caspase activation and subsequent mitochondrial damage. Molecular ordering of these phenomena reveals that mitotic catastrophe occurs in a p53-independent manner and involves a primary activation of caspase-2, upstream of cytochrome c release, followed by caspase-3 activation and chromatin condensation. Suppression of caspase-2 by RNA interference or pseudosubstrate inhibitors as well as blockade of the mitochondrial membrane permeabilization prevent the mitotic catastrophe and allow cells to further proceed the cell cycle beyond the metaphase, leading to asymmetric cell division. Heterokarya generated by the fusion of nonsynchronized cells can be driven to divide into three or more daughter cells when Chk2 and caspases are simultaneously inhibited. Such multipolar divisions, resulting from suppressed mitotic catastrophe, lead to the asymmetric distribution of cytoplasm (anisocytosis), DNA (anisokaryosis) and chromosomes (aneuploidy). Similarly, in a model of DNA damage-induced mitotic catastrophe, suppression of apoptosis leads to the generation of aneuploid cells. Our findings delineate a molecular pathway through which DNA damage, failure to arrest the cell cycle and inhibition of apoptosis can favor the occurrence of cytogenetic abnormalities that are likely to participate in oncogenesis.

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Abbreviations

Casp-2a:

activated caspase-2

Casp-3a:

activated caspase-3

Cdk1:

cyclin dependent kinase-1

Cyt. c:

cytochrome c

DBH:

debromohymenialdisine

DN:

dominant negative

Env:

envelope glycoprotein complex

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

HIV:

human immunodeficiency virus

KG:

karyogamy

MMP:

mitochondrial membrane permeabilization

mTOR:

mammalian target of rapamycin

p53S15P:

p53 with phosphorylated serine 15

RNAi:

RNA interference

siRNA:

small interfering RNA

SC:

single cell

Syn:

syncytia

Z-VAD.fmk:

N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone

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Acknowledgements

We thank Dr Bernd Vogelstein (Johns Hopkins Oncology Center, Baltimore, MD for cell lines, Dr. Victor Goldmacher (ImmunoGen, Cambridge, MA, USA), Dr. Thierry Soussi (Institut Curie, Paris, France), Dr Guy Salvesen (Burnham Institute, La Jolla, CA, USA) for cDNA constructs; Didier Métivier, Nathanael Larochette (CNRS, Villejuif, France) for assistance, and the NIH AIDS reagents program (Bethesda, MD, USA) for cell lines. This work has been supported by a special grant from LNC, as well as grants from ANRS, FRM, European Commission (QLG1-CT-1999-00739 and Contract No. QLK3-CT-20002-01956) (to GK)

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Correspondence to Guido Kroemer.

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Castedo, M., Perfettini, JL., Roumier, T. et al. Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy. Oncogene 23, 4362–4370 (2004). https://doi.org/10.1038/sj.onc.1207572

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