ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration

EMBO J. 2017 Jul 14;36(14):2161-2176. doi: 10.15252/embj.201696082. Epub 2017 Jun 12.

Abstract

After DNA damage, the cell cycle is arrested to avoid propagation of mutations. Arrest in G2 phase is initiated by ATM-/ATR-dependent signaling that inhibits mitosis-promoting kinases such as Plk1. At the same time, Plk1 can counteract ATR-dependent signaling and is required for eventual resumption of the cell cycle. However, what determines when Plk1 activity can resume remains unclear. Here, we use FRET-based reporters to show that a global spread of ATM activity on chromatin and phosphorylation of ATM targets including KAP1 control Plk1 re-activation. These phosphorylations are rapidly counteracted by the chromatin-bound phosphatase Wip1, allowing cell cycle restart despite persistent ATM activity present at DNA lesions. Combining experimental data and mathematical modeling, we propose a model for how the minimal duration of cell cycle arrest is controlled. Our model shows how cell cycle restart can occur before completion of DNA repair and suggests a mechanism for checkpoint adaptation in human cells.

Keywords: ATM; ATR; G2; Plk1; checkpoint recovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Chromatin / metabolism*
  • Fluorescence Resonance Energy Transfer
  • G2 Phase Cell Cycle Checkpoints*
  • Humans
  • Models, Biological
  • Models, Theoretical
  • Phosphorylation
  • Protein Interaction Mapping
  • Protein Phosphatase 2C / metabolism*
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Repressor Proteins / metabolism
  • Tripartite Motif-Containing Protein 28

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • TRIM28 protein, human
  • Tripartite Motif-Containing Protein 28
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • PPM1D protein, human
  • Protein Phosphatase 2C