A FOXO-dependent replication checkpoint restricts proliferation of damaged cells.

Autor:	Hornsveld M; Oncode Institute, Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 Leiden, the Netherlands; Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 Utrecht, the Netherlands. Electronic address: m.hornsveld@lumc.nl., Feringa FM; Oncode Institute, Division of Cell Biology, Netherlands Cancer Institute, 1066 Amsterdam, the Netherlands; Department of Molecular and Cellular Neurobiology, Faculty of Science, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 Amsterdam, the Netherlands., Krenning L; Oncode Institute, Division of Cell Biology, Netherlands Cancer Institute, 1066 Amsterdam, the Netherlands., van den Berg J; Oncode Institute, Division of Cell Biology, Netherlands Cancer Institute, 1066 Amsterdam, the Netherlands; Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 Utrecht, the Netherlands., Smits LMM; Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 Utrecht, the Netherlands., Nguyen NBT; Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 Utrecht, the Netherlands., Rodríguez-Colman MJ; Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 Utrecht, the Netherlands., Dansen TB; Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 Utrecht, the Netherlands., Medema RH; Oncode Institute, Division of Cell Biology, Netherlands Cancer Institute, 1066 Amsterdam, the Netherlands., Burgering BMT; Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 Utrecht, the Netherlands. Electronic address: b.m.t.burgering@umcutrecht.nl.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Jan 26; Vol. 34 (4), pp. 108675.
DOI:	10.1016/j.celrep.2020.108675
Abstrakt:	DNA replication is challenged by numerous exogenous and endogenous factors that can interfere with the progression of replication forks. Substantial accumulation of single-stranded DNA during DNA replication activates the DNA replication stress checkpoint response that slows progression from S/G2 to M phase to protect genomic integrity. Whether and how mild replication stress restricts proliferation remains controversial. Here, we identify a cell cycle exit mechanism that prevents S/G2 phase arrested cells from undergoing mitosis after exposure to mild replication stress through premature activation of the anaphase promoting complex/cyclosome (APC/C CDH1 ). We find that replication stress causes a gradual decrease of the levels of the APC/C CDH1 inhibitor EMI1/FBXO5 through Forkhead box O (FOXO)-mediated inhibition of its transcription factor E2F1. By doing so, FOXOs limit the time during which the replication stress checkpoint is reversible and thereby play an important role in maintaining genomic stability. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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