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 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.

Phosphorylation by Aurora B kinase regulates caspase-2 activity and function

“…Importantly, cells from mice harboring catalytic-dead caspase-2 (CASP2 C320S ) also show increased aneuploidy following prolonged mitotic arrest 12 . These findings suggest that the activation and enzymatic activity of caspase-2 are required to mediate apoptosis of aneuploid cells.…”

Caspase 2 in mitotic catastrophe: The terminator of aneuploid and tetraploid cells

“…16 Dawar et al performed time-lapse imaging and cytogenetic analyses of primary splenocytes from Casp2 ¡/¡ mice and CASP2-depleted human cancer cells to show that the absence of CASP2 promoted mitotic slippage as well as the survival of the resulting multinucleated cells that were able to resume proliferation in clonogenic assays. These results suggest that CASP2 may also contribute to SAC signaling, an intriguing hypothesis that requires further confirmation.…”

“…13 Three recent studies shed light on the mechanism of, and the signal responsible for, CASP2 activation during mitotic catastrophe unveiling the existence of a tight connection between CASP2 and the p53 pathway. [14][15][16] By analyzing colorectal cancers and cell lines displaying high levels of CIN, either at the baseline or upon the pharmacological abrogation of the SAC or increase of replication stress, Lopez-Garcia and colleagues identified a novel mechanism of tolerance to non-diploidy based on the downregulation of CASP2 expression.…”

“…1). 16 It will be important to further explore this model of mitotic catastrophe to elucidate the nature of the signal activating CASP2 and to clarify whether p53 plays a role upstream or downstream of CASP2 activation.…”

The nucleolus: A new home for the PIDDosome

“…NPM1 and caspase-2 driven apoptosis from the nucleolus could also play a key role in this process, since Kumar and colleagues recently showed that caspase-2 induces apoptosis to remove aneuploid cells. 6 Continued efforts to unravel the contributions of the nucleolar complex to apoptosis or regulation of proliferation will be imperative to determining how caspase-2 protects from aneuploidy.…”