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A FOXO-dependent replication checkpoint restricts proliferation of damaged cells

Marten Hornsveld1, Femke M Feringa2, Lenno Krenning3

  • 1Oncode 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.

Cell Reports
|January 27, 2021
PubMed

Insights

Mild replication stress triggers cell cycle exit by prematurely activating the anaphase promoting complex/cyclosome (APC/CCDH1). Forkhead box O (FOXO) proteins reduce replication stress, protecting genomic stability.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genomics

Background:

  • DNA replication is crucial for genomic integrity but faces challenges from various factors.
  • Replication stress activates checkpoints to protect the genome, but its effect on cell proliferation is debated.

Purpose of the Study:

  • To investigate the mechanism by which mild replication stress restricts cell proliferation.
  • To identify the role of the anaphase promoting complex/cyclosome (APC/CCDH1) in response to replication stress.

Main Methods:

  • Analysis of cell cycle progression under mild replication stress.
  • Investigating the regulation of EMI1/FBXO5 levels and APC/CCDH1 activity.
  • Studying the role of Forkhead box O (FOXO) proteins and E2F1 in the response.

Main Results:

  • Mild replication stress leads to premature activation of APC/CCDH1, causing cell cycle exit.
  • Replication stress decreases EMI1/FBXO5 levels via FOXO-mediated inhibition of E2F1.
  • FOXO proteins limit the reversibility of the replication stress checkpoint.

Conclusions:

  • A novel cell cycle exit mechanism is identified, preventing mitosis in cells experiencing mild replication stress.
  • FOXO proteins play a critical role in maintaining genomic stability by regulating the replication stress response.
Keywords:
DNA damage checkpointDNA replication stressEMI1FOXOcell cycle exitcheckpoint recoverygenomic instabilitysenescence

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