Homeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing

Nat Commun. 2014 Jun 4;5:4048. doi: 10.1038/ncomms5048.

Abstract

The G2 checkpoint monitors DNA damage, preventing mitotic entry until the damage can be resolved. The mechanisms controlling checkpoint recovery are unclear. Here, we identify non-genetic heterogeneity in the fidelity and timing of damage-induced G2 checkpoint enforcement in individual cells from the same population. Single-cell fluorescence imaging reveals that individual damaged cells experience varying durations of G2 arrest, and recover with varying levels of remaining checkpoint signal or DNA damage. A gating mechanism dependent on polo-like kinase-1 (PLK1) activity underlies this heterogeneity. PLK1 activity continually accumulates from initial levels in G2-arrested cells, at a rate inversely correlated to checkpoint activation, until it reaches a threshold allowing mitotic entry regardless of remaining checkpoint signal or DNA damage. Thus, homeostatic control of PLK1 by the dynamic opposition between checkpoint signalling and pro-mitotic activities heterogeneously enforces the G2 checkpoint in each individual cell, with implications for cancer pathogenesis and therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded*
  • DNA Damage
  • G2 Phase Cell Cycle Checkpoints*
  • Genetic Heterogeneity
  • Homeostasis
  • Humans
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Time Factors

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1