Figure 1. Perturbations of mitotic protein machinery lead to chromosome instability.

During mitosis condensed chromosomes (violet) form stable kinetochore (blue)-microtubule (green) attachments, align on the metaphase plate, and then segregate to opposite spindle poles in anaphase. Gene dosage imbalance can lead to defects in spindle assembly checkpoint and proper formation of the mitotic spindle. Spindle assembly checkpoint is a surveillance mechanism that generates the “delay anaphase” signal in response to unattached kinetochores. Defects in spindle assembly checkpoint allow anaphase to proceed despite the presence of a misaligned chromosome (yellow) whose kinetochores (red) are not stably attached to microtubules. Unattached sister chromatids cannot segregate to opposite spindle poles during anaphase and wind up in one of the daughter cells. Merotelically attached chromosome (magenta), where a single kinetochore is attached to microtubules from both spindle poles, can be a consequence of defects in mitotic spindle formation and microtubule dynamics. Merotelic attachments can evade mitotic spindle checkpoint surveillance but form lagging chromosomes that tend to missegregate and can disrupt the last step in cytokinesis - abscission. The failure to segregate properly leads to altered chromosome copy number in daughter cells: both copies of the unattached or lagging chromosomes end up in one cell while the other cell lacks a copy. Unattached and lagging chromosomes can form micronuclei – detached minute nuclei consisting of de-condensed DNA from missegregated chromosomes surrounded by the nuclear membrane. Micronuclei are prone to having defects in DNA replication, which adds to genomic instability. Chromosome missegregations, as well as protein dosage imbalances, can lead to cytokinesis failure and formation of tetraploid cells which are binucleate and contain twice the number of centrosomes (orange) as diploid cells. Tetraploid cells can also have micronuclei.