TY - JOUR T1 - An ATM/Wip1-dependent timer controls the minimal duration of a DNA-damage mediated cell cycle arrest JF - bioRxiv DO - 10.1101/042119 SP - 042119 AU - Himjyot Jaiswal AU - Jan Benada AU - Erik Müllers AU - Karen Akopyan AU - Kamila Burdova AU - Tobias Koolmeister AU - Thomas Helleday AU - René H Medema AU - Libor Macurek AU - Arne Lindqvist Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/03/02/042119.abstract N2 - 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. ER -