A FOXO-dependent replication checkpoint restricts proliferation of damaged cells

Marten Hornsveld; Femke M. Feringa; Lenno Krenning; Jeroen van den Berg; Lydia M.M. Smits; Nguyen B.T. Nguyen; Maria J. Rodríguez-Colman; Tobias B. Dansen; René H. Medema; Boudewijn M.T. Burgering

doi:10.1016/j.celrep.2020.108675

A FOXO-dependent replication checkpoint restricts proliferation of damaged cells

Marten Hornsveld^*, Femke M. Feringa, Lenno Krenning, Jeroen van den Berg, Lydia M.M. Smits, Nguyen B.T. Nguyen, Maria J. Rodríguez-Colman, Tobias B. Dansen, René H. Medema, Boudewijn M.T. Burgering

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	108675
Pages (from-to)	1-15
Number of pages	15
Journal	Cell Reports
Volume	34
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2020.108675
Publication status	Published - 26 Jan 2021

Keywords

cell cycle exit
checkpoint recovery
DNA damage checkpoint
DNA replication stress
EMI1
FOXO
genomic instability
senescence

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "A FOXO-dependent replication checkpoint restricts proliferation of damaged cells",

abstract = "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/CCDH1). We find that replication stress causes a gradual decrease of the levels of the APC/CCDH1 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.",

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AU - Hornsveld, Marten

AU - Feringa, Femke M.

AU - Krenning, Lenno

AU - van den Berg, Jeroen

AU - Smits, Lydia M.M.

AU - Nguyen, Nguyen B.T.

AU - Rodríguez-Colman, Maria J.

AU - Dansen, Tobias B.

AU - Medema, René H.

AU - Burgering, Boudewijn M.T.

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N2 - 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/CCDH1). We find that replication stress causes a gradual decrease of the levels of the APC/CCDH1 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.

AB - 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/CCDH1). We find that replication stress causes a gradual decrease of the levels of the APC/CCDH1 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.

KW - cell cycle exit

KW - checkpoint recovery

KW - DNA damage checkpoint

KW - DNA replication stress

KW - EMI1

KW - FOXO

KW - genomic instability

KW - senescence

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A FOXO-dependent replication checkpoint restricts proliferation of damaged cells

Abstract

Keywords

UN SDGs

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