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 journalArticleAcademicpeer-review

2 Citations (Scopus)
9 Downloads (Pure)

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.

Original languageEnglish
Article number108675
JournalCell Reports
Volume34
Issue number4
DOIs
Publication statusPublished - 26 Jan 2021

Keywords

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

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