Short- and long-term effects of chromosome mis-segregation and aneuploidy

Key Points Aneuploidy is defined as an abnormal karyotype that is not a multiple of the haploid complement. Chromosome mis-segregation causes DNA damage. Micronuclei form during chromosome mis-segregation. Chromosomes within micronuclei are under-replicated and undergo chromothripsis. Chromosome mis-segregation leads to p53 activation. The complex phenotypes caused by aneuploidy are produced by changes in the dosage of specific genes and a generic aneuploidy-associated stress response. Aneuploidy causes proteotoxic stress and impairs proliferation. Aneuploidy is a hallmark of cancer but the relationship between aneuploidy and cancer is complex. Depending on the context, aneuploidy can promote or antagonize malignant transformation. Aneuploidy, which results from chromosome mis-segregation, is a hallmark of cancer, but it can also inhibit tumorigenesis. Recent studies on the short- and long-term consequences of aneuploidy, which are caused by gene-specific effects and a stereotypic aneuploidy stress response, provide insights into this contradictory role in tumorigenesis. Dividing cells that experience chromosome mis-segregation generate aneuploid daughter cells, which contain an incorrect number of chromosomes. Although aneuploidy interferes with the proliferation of untransformed cells, it is also, paradoxically, a hallmark of cancer, a disease defined by increased proliferative potential. These contradictory effects are also observed in mouse models of chromosome instability (CIN). CIN can inhibit and promote tumorigenesis. Recent work has provided insights into the cellular consequences of CIN and aneuploidy. Chromosome mis-segregation per se can alter the genome in many more ways than just causing the gain or loss of chromosomes. The short- and long-term effects of aneuploidy are caused by gene-specific effects and a stereotypic aneuploidy stress response. Importantly, these recent findings provide insights into the role of aneuploidy in tumorigenesis.