Original Article

Oncogene (2017) 36, 2704–2714; doi:10.1038/onc.2016.423; published online 19 December 2016

Caspase-2-mediated cell death is required for deleting aneuploid cells
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S Dawar1, Y Lim1, J Puccini1,2, M White3, P Thomas3, L Bouchier-Hayes4, D R Green5, L Dorstyn1,6 and S Kumar1,6

  1. 1Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
  2. 2Departments of Biochemistry and Molecular Pharmacology and Medicine, New York University, New York City, NY, USA
  3. 3SA Genome Editing Facility, School of Biological Sciences and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
  4. 4Department of Pediatrics-Hematology, Baylor College of Medicine, Houston, TX, USA
  5. 5Immunology Department, St Jude Children’s Research Hospital, Memphis, TN, USA

Correspondence: Professor S Kumar, Centre for Cancer Biology, University of South Australia, Frome Road, Adelaide 5001, SA, Australia. E-mail: sharad.kumar@unisa.edu.au

6Co-senior authors.

Received 27 May 2016; Revised 6 September 2016; Accepted 3 October 2016
Advance online publication 19 December 2016

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Abstract

Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated in maintenance of chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2/) mice develop normally but show premature ageing-related traits and when challenged by certain stressors, succumb to enhanced tumour development and aneuploidy. To test how caspase-2 protects against chromosomal instability, we utilized an ex vivo system for aneuploidy where primary splenocytes from Casp2/ mice were exposed to anti-mitotic drugs and followed up by live cell imaging. Our data show that caspase-2 is required for deleting mitotically aberrant cells. Acute silencing of caspase-2 in cultured human cells recapitulated these results. We further generated Casp2C320S mutant mice to demonstrate that caspase-2 catalytic activity is essential for its function in limiting aneuploidy. Our results provide direct evidence that the apoptotic activity of caspase-2 is necessary for deleting cells with mitotic aberrations to limit aneuploidy.

Abbreviations:

ATM, Ataxia telangiectasia mutated; BUB3, budding uninhibited by benzimidazoles 3 homolog; CDC20, Cell Division Cycle 20; ConA, Concanavalin A; Mad2, mitotic arrest deficient 2; MEFs, murine embryonic fibroblasts; MOMP, mitochondrial outer membrane permeabilization; PLK1-I, Polo-Like kinase 1 inhibitor; SAC, spindle-assembly checkpoint.