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Simple Summary: Errors in the distribution of genetic information, contained in structures referred to as chromosomes, which are made up by DNA and proteins, during a cell division (mitosis) can cause developmental defects and contribute to malignant disease. To prevent the potentially detrimental consequences of unfaithful separation of chromosomes, or parts thereof, a process referred to as chromosomal instability (CIN), cells have developed different solutions. One such solution is the removal of chromosomally instable cells by suicide. This is achieved by the activation of a cell-intrinsic program, termed apoptosis. Lost cells are usually replenished by those that achieve the precise distribution of genetic information between daughter cells, in order to maintain a healthy balance in tissues (homeostasis). Mis-segregation of chromosomes reduces cellular fitness, e.g., due to accumulation of DNA damage during the process or imbalances in cellular protein levels arising from inheriting an uneven number of chromosomes (aneuploidy). All these events can trigger activation of the apoptosis machinery. Losing the ability to commit cellular suicide under such conditions can contribute to the rise of cancer, or foster drug-resistance in established tumours during treatment. Here, we discuss the mechanisms involved that promote cellular suicide in cells that show CIN or aneuploidy and how such cells may eventually manage to escape cell death. Aneuploidy is the gain or loss of entire chromosomes, chromosome arms or fragments. Over 100 years ago, aneuploidy was described to be a feature of cancer and is now known to be present in 68–90% of malignancies. Aneuploidy promotes cancer growth, reduces therapy response and frequently worsens prognosis. Chromosomal instability (CIN) is recognized as the main cause of aneuploidy. CIN itself is a dynamic but stochastic process consisting of different DNA content-altering events. These can include impaired replication fidelity and insufficient clearance of DNA damage as well as chromosomal mis-segregation, micronuclei formation, chromothripsis or cytokinesis failure. All these events can disembogue in segmental, structural and numerical chromosome alterations. While low levels of CIN can foster malignant disease, high levels frequently trigger cell death, which supports the "aneuploidy paradox" that refers to the intrinsically negative impact of a highly aberrant karyotype on cellular fitness. Here, we review how the cellular response to CIN and aneuploidy can drive the clearance of karyotypically unstable cells through the induction of apoptosis. Furthermore, we discuss the different modes of p53 activation triggered in response to mitotic perturbations that can potentially trigger CIN and/or aneuploidy. [ABSTRACT FROM AUTHOR]

Centrosomes are membrane-less organelles that orchestrate a wide array of biological functions by acting as microtubule organizing centers. Here, we report that caspase-2-driven apoptosis is elicited in blood cells failing cytokinesis and that extra centrosomes are necessary to trigger this cell death. Activation of caspase-2 depends on the PIDDosome multi-protein complex, and priming of PIDD1 at extra centrosomes is necessary for pathway activation. Accordingly, loss of its centrosomal adapter, ANKRD26, allows for cell survival and unrestricted polyploidization in response to cytokinesis failure. Mechanistically, cell death is initiated upstream of mitochondria via caspase-2-mediated processing of the BCL2 family protein BID, driving BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP). Remarkably, BID-deficient cells enforce apoptosis by engaging p53-dependent proapoptotic transcriptional responses initiated by caspase-2. Consistently, BID and MDM2 act as shared caspase-2 substrates, with BID being kinetically favored. Our findings document that the centrosome limits its own unscheduled duplication by the induction of PIDDosome-driven mitochondrial apoptosis to avoid potentially pathogenic polyploidization events. [ABSTRACT FROM AUTHOR]