Short description
Jaiswal2017 - Cell cycle arrest

This model is described in the article:

Jaiswal H, Benada J, Müllers E, Akopyan K, Burdova K, Koolmeister T, Helleday T, Medema RH, Macurek L, Lindqvist A.
EMBO J. 2017 Jul; 36(14): 2161-2176

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.

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Format
SBML (L3V1)
Related Publication
  • ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration.
  • Jaiswal H, Benada J, Müllers E, Akopyan K, Burdova K, Koolmeister T, Helleday T, Medema RH, Macurek L, Lindqvist A
  • The EMBO journal , 7/ 2017 , Volume 36 , pages: 2161-2176
  • Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
  • 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.
Contributors
Karen Akopyan

Metadata information

hasTaxon
Taxonomy Homo sapiens
isDescribedBy
occursIn
Curation status
Curated
Original model(s)
G2_checkpoint_minimal_duration
Name Description Size Actions

Model files

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  • Model originally submitted by : Karen Akopyan
  • Submitted: Apr 3, 2017 9:00:49 AM
  • Last Modified: Aug 1, 2017 3:51:33 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Aug 1, 2017 3:51:33 PM
    • Submitted by: Karen Akopyan
    • With comment: Current version of Jaiswal2017 - Cell cycle arrest
  • Version: 1 public model Download this version
    • Submitted on: Apr 3, 2017 9:00:49 AM
    • Submitted by: Karen Akopyan
    • With comment: Original import of New Model
Curator's comment:
(added: 01 Aug 2017, 15:39:05, updated: 01 Aug 2017, 15:39:05)
Figure 7B, lower panel (full model) is reproduced using CellDesigner 4.4. Legends: Damage( damage), Timeract (ATM), CellCact (Plk1) and Effectoract (ATR)