The chromatin-binding domain of Ki-67 together with p53 protects human chromosomes from mitotic damage

Significance Ki-67 is a clinically important tumor proliferation marker protein. Ki-67 contributes to the three-dimensional organization of heterochromatin during interphase of the cell cycle, and also coats and shapes condensed chromosomes during mitosis. Here, we show that acute depletion of Ki-67 in human cells causes DNA damage as cells traverse mitosis. When the tumor suppressor protein p53 is codepleted with Ki-67, multiple hallmarks of genome instability arise, including anaphase chromosome bridges, followed by the appearance of micronuclei. The C-terminal chromatin-binding domain of Ki-67 is sufficient for resistance to this damage. These studies uncover a factor for genome maintenance and identify a protective protein domain.