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bioRxiv · 10.1101/042119

An ATM/Wip1-dependent timer controls the minimal duration of a DNA-damage mediated cell cycle arrest

Himjyot Jaiswal·Jan Benada·Erik Mullers·Karen Akopyan·Kamila Burdova·Tobias Koolmeister·Thomas Helleday·Rene Medema·Libor Macurek·Arne Lindqvist
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Abstract

After DNA damage, the cell cycle is arrested to avoid propagation of mutations. In G2 phase, the arrest is initiated by ATM/ATR-dependent signalling that blocks mitosis-promoting kinases as Plk1. Interestingly, Plk1 can counteract ATR-dependent signalling 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 targets including Kap1 control Plk1 re-activation. These phosphorylations are rapidly counteracted by the chromatin-bound phosphatase Wip1, allowing a cell cycle restart despite persistent ATM activity present at DNA lesions. Combining experimental data and mathematical modelling we propose that the minimal duration of a cell cycle arrest is controlled by a timer. Our model shows how cell cycle re-start can occur before completion of DNA repair and suggests a mechanism for checkpoint adaptation in human cells.

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Himjyot Jaiswal, Jan Benada, Erik Mullers, Karen Akopyan, Kamila Burdova, Tobias Koolmeister, Thomas Helleday, Rene Medema, Libor Macurek, Arne Lindqvist. 2016-03-02. An ATM/Wip1-dependent timer controls the minimal duration of a DNA-damage mediated cell cycle arrest. https://doi.org/10.1101/042119

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