ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration.
EMBO J
; 36(14): 2161-2176, 2017 07 14.
Article
em En
| MEDLINE
| ID: mdl-28607002
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cromatina
/
Proteínas Proto-Oncogênicas
/
Proteínas Serina-Treonina Quinases
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Proteínas de Ciclo Celular
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Pontos de Checagem da Fase G2 do Ciclo Celular
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Proteínas Mutadas de Ataxia Telangiectasia
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Proteína Fosfatase 2C
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article