ATM/Wip1 activities at chromatin control Plk1 re‐activation to determine G2 checkpoint duration |
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Authors: | Himjyot Jaiswal Karen Akopyan Kamila Burdova Tobias Koolmeister Thomas Helleday René H Medema Libor Macurek Arne Lindqvist |
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Institution: | 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. Department of Medical Biochemistry and Biophysics, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden;4. Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands;5. Laboratory of Cancer Cell Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech RepublicThese authors contributed equally to this work;6. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, SwedenThese authors contributed equally to this work |
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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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Keywords: |
ATM
ATR
checkpoint recovery G2 Plk1 |
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