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

Proc Natl Acad Sci U S A. 2021 Aug 10;118(32):e2021998118. doi: 10.1073/pnas.2021998118.


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.

Keywords: DNA damage; chromatin; mitosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase
  • Binding Sites
  • Cell Line
  • Chromatin / metabolism*
  • Chromosomes, Human*
  • DNA Damage
  • Genomic Instability
  • Humans
  • Ki-67 Antigen / genetics
  • Ki-67 Antigen / metabolism*
  • Mitosis
  • Protein Domains
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor p53-Binding Protein 1 / genetics
  • Tumor Suppressor p53-Binding Protein 1 / metabolism


  • Chromatin
  • Ki-67 Antigen
  • TP53 protein, human
  • TP53BP1 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor p53-Binding Protein 1