Figure 2.

Mitotic errors can generate DNA damage. (A) Lagging chromosomes in anaphase can acquire DNA damage directly by being trapped in the spindle midzone during cytokinesis. In addition, lagging chromosomes that are partitioned into micronuclei can acquire DNA damage in interphase of the subsequent cell cycle. Extensive damage leads to chromosome shattering, a phenomenon known as chromothripsis, which results in the production of highly localized chromosome rearrangements and/or the production of double-minute chromosomes. (B) Extensive shortening of telomeres (telomere crisis) can result in the end-to-end fusion of two telomeres and the generation of a dicentric chromosome. Dicentric chromosomes can attach to opposite sides of the cell and be pulled apart during mitosis, resulting in a chromatin bridge that connects the two daughter nuclei. The nuclear membrane surrounding the bridging DNA ruptures in interphase, and the exposed DNA can be subject to cleavage by a cytoplasmic nuclease to resolve the bridge. The DNA exposed to the cytoplasm may undergo chromothriptic-like chromosome rearrangements and/or hypermutation generated by APOBEC cytidine deaminases. (C) DNA entanglements between sister chromatids can form at underreplicated regions or as a result of persistent DNA catenation. If these linkages are not resolved by topoisomerases and helicases, they can form ultrafine DNA bridges that connect the segregating sister chromatids in anaphase. Ultrafine bridges can lead to cytokinesis failure, resulting in a binucleated cell, or be broken during anaphase, creating DNA damage and micronuclei.