Apoptosis as a Barrier against CIN and Aneuploidy

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. ABSTRACT: 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.