Journal
EMBO JOURNAL
Volume 36, Issue 14, Pages 2161-2176Publisher
WILEY
DOI: 10.15252/embj.201696082
Keywords
ATM; ATR; checkpoint recovery; G2; Plk1
Categories
Funding
- Swedish Research Council
- Swedish Foundation for Strategic Research
- Swedish Cancer Society
- Swedish Childhood Cancer Foundation
- Vinnova
- Grant Agency of the Czech Republic [13-18392S]
- Norwegian Financial Mechanism [7F14061]
- Wenner-Gren Foundation
- Grant Agency of the Charles University [836613]
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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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