biostudies-literatureGarwain OHHS | NIH | National Institute of General Medical Sciencese2021998118https://www.ebi.ac.uk/biostudies/studies/S-EPMC8364191biostudies-literatureUnknown118(32)Vertebrate mammals express a protein called Ki-67 which is most widely known as a clinically useful marker of highly proliferative cells. Previous studies of human cells indicated that acute depletion of Ki-67 can elicit a delay at the G1/S boundary of the cell cycle, dependent on induction of the checkpoint protein p21. Consistent with those observations, we show here that acute Ki-67 depletion causes hallmarks of DNA damage, and the damage occurs even in the absence of checkpoint signaling. This damage is not observed in cells traversing S phase but is instead robustly detected in mitotic cells. The C-terminal chromatin-binding domain of Ki-67 is necessary and sufficient to protect cells from this damage. We also observe synergistic effects when Ki-67 and p53 are simultaneously depleted, resulting in increased levels of chromosome bridges at anaphase, followed by the appearance of micronuclei. Therefore, these studies identify the C terminus of Ki-67 as an important module for genome stability.Proceedings of the National Academy of Sciences of the United States of AmericaThe chromatin-binding domain of Ki-67 together with p53 protects human chromosomes from mitotic damage.PMC8364191R35 GM127035Kaufman PDZhu LJIyer DRGarwain OLi RSun XfalseThe chromatin-binding domain of Ki-67 together with p53 protects human chromosomes from mitotic damage.Vertebrate mammals express a protein called Ki-67 which is most widely known as a clinically useful marker of highly proliferative cells. Previous studies of human cells indicated that acute depletion of Ki-67 can elicit a delay at the G1/S boundary of the cell cycle, dependent on induction of the checkpoint protein p21. Consistent with those observations, we show here that acute Ki-67 depletion causes hallmarks of DNA damage, and the damage occurs even in the absence of checkpoint signaling. This damage is not observed in cells traversing S phase but is instead robustly detected in mitotic cells. The C-terminal chromatin-binding domain of Ki-67 is necessary and sufficient to protect cells from this damage. We also observe synergistic effects when Ki-67 and p53 are simultaneously depleted, resulting in increased levels of chromosome bridges at anaphase, followed by the appearance of micronuclei. Therefore, these studies identify the C terminus of Ki-67 as an important module for genome stability.2021-01-01T00:00:00Z2021 Aug2025-04-04T19:17:11.333Z2025-04-04T19:17:11.333ZS-EPMC83641913435390310.1073/pnas.2021998118