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Jaiswal2017 - Cell cycle arrest


ABSTRACT: Jaiswal2017 - Cell cycle arrest This model is described in the article: 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. 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. This model is hosted on BioModels Database and identified by: BIOMD0000000641. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Karen Akopyan  

PROVIDER: BIOMD0000000641 | BioModels | 2014-03-28

REPOSITORIES: BioModels

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

Jaiswal Himjyot H   Benada Jan J   Müllers Erik E   Akopyan Karen K   Burdova Kamila K   Koolmeister Tobias T   Helleday Thomas T   Medema René H RH   Macurek Libor L   Lindqvist Arne A  

The EMBO journal 20170612 14


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 phosphorylati  ...[more]

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