title: Caspase-2-mediated cell death is required for deleting aneuploid cells.
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 Casp2C320Smutant 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.
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Dawar
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Lim
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia.|Departments of Biochemistry and Molecular Pharmacology and Medicine, New York University, New York City, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Puccini
authors.affiliation: SA Genome Editing Facility, School of Biological Sciences and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
authors.forename: M
authors.initials: M
authors.lastname: White
authors.affiliation: SA Genome Editing Facility, School of Biological Sciences and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Department of Pediatrics-Hematology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bouchier-Hayes
authors.affiliation: Immunology Department, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Dorstyn
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053143:Caspase 2 / Q000235:genetics* / Q000378:metabolism; D043171:Chromosomal Instability / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics
chemical_list: D053143:Caspase 2