Related Experiment Video
Updated: Feb 28, 2026
Study of the DNA Damage Checkpoint using Xenopus Egg Extracts
Published on: November 5, 2012
ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration
Himjyot Jaiswal1, Jan Benada2,3, Erik Müllers1
1Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
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.
Insights
Cell cycle arrest after DNA damage is controlled by ATM signaling and the phosphatase Wip1. This mechanism allows cell cycle restart, even before DNA repair is complete, enabling checkpoint adaptation.
Area of Science:
- Cellular biology
- Molecular oncology
- DNA damage response
Background:
- DNA damage triggers cell cycle arrest to prevent mutations.
- ATM/ATR signaling inhibits Plk1, a key kinase for cell cycle resumption.
- The precise timing of Plk1 reactivation remains poorly understood.
Purpose of the Study:
- To elucidate the regulatory mechanisms controlling Plk1 reactivation after DNA damage.
- To understand how cells determine the minimal duration of cell cycle arrest.
- To investigate checkpoint adaptation in human cells.
Main Methods:
- Utilized Förster Resonance Energy Transfer (FRET)-based reporters to monitor kinase activity.
- Investigated chromatin-bound ATM activity and phosphorylation of ATM targets.
- Employed mathematical modeling alongside experimental data.
Main Results:
- Global chromatin spread of ATM activity and KAP1 phosphorylation regulate Plk1 reactivation.
- The phosphatase Wip1 rapidly reverses these phosphorylations, enabling cell cycle restart.
- Cell cycle restart can occur despite persistent ATM activity at DNA lesions.
Conclusions:
- A model is proposed for controlling the minimal duration of cell cycle arrest.
- Checkpoint adaptation allows cell cycle restart before complete DNA repair.
- This study reveals a novel mechanism for regulating cell cycle checkpoints in human cells.
Related Concept Videos
02:36DNA Damage can Stall the Cell Cycle
02:36DNA Damage Can Stall the Cell Cycle
02:19The Spindle Assembly Checkpoint
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
02:37Restarting Stalled Replication Forks
02:34Inhibition of Cdk Activity
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...