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

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

Author information

1
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
2
Laboratory of Cancer Cell Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
3
Faculty of Science, Charles University in Prague, Prague, Czech Republic.
4
Department of Medical Biochemistry and Biophysics, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
5
Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
6
Laboratory of Cancer Cell Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic libor.macurek@img.cas.cz arne.lindqvist@ki.se.
7
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden libor.macurek@img.cas.cz arne.lindqvist@ki.se.

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

PMID:
28607002
PMCID:
PMC5510006
DOI:
10.15252/embj.201696082
[Indexed for MEDLINE]
Free PMC Article

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