Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation

Nat Commun. 2024 Dec 30;15(1):10782. doi: 10.1038/s41467-024-54922-7.

Abstract

Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, and its activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate mitotic PLK1 remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation.

MeSH terms

  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Checkpoint Kinase 2* / genetics
  • Checkpoint Kinase 2* / metabolism
  • Chromosome Segregation*
  • DNA Damage
  • DNA Repair
  • Genomic Instability
  • HeLa Cells
  • Humans
  • Mitosis*
  • Phosphorylation
  • Polo-Like Kinase 1*
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Proto-Oncogene Proteins* / genetics
  • Proto-Oncogene Proteins* / metabolism

Substances

  • Polo-Like Kinase 1
  • Checkpoint Kinase 2
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Cell Cycle Proteins
  • CHEK2 protein, human