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Slx4 and Fun30/SMARCAD1 coordinate S-phase checkpoint regulation and replication fork protection in response to

Mathilde Courtes1, Thierry Boissière1, Antoine Barthe1

  • 1Institut de Génétique Humaine (IGH), Univ Montpellier, CNRS, Montpellier 34090, France.

Nucleic Acids Research
|April 14, 2026
PubMed

Insights

Checkpoint signaling dampening is crucial for completing DNA replication and maintaining genome stability during replication stress. This process involves specific DNA repair factors that manage stalled replication forks.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Replication stress drives genomic instability and diseases like cancer.
  • The S-phase checkpoint manages replication obstacles and cell cycle progression.
  • DNA-protein crosslinks, e.g., from camptothecin (CPT), are a major source of replication stress.

Purpose of the Study:

  • Investigate the S-phase checkpoint response to CPT-induced replication stress.
  • Determine the mechanisms of checkpoint activation and deactivation.
  • Understand how checkpoint signaling impacts DNA replication and genome stability.

Main Methods:

  • Locus-specific analysis of checkpoint signaling.
  • Investigating the roles of DNA repair factors (Slx4, Fun30, Exo1) and checkpoint mediator (Rad9).
  • Assessing DNA replication completion and cell viability.

Main Results:

  • Both activation and timely deactivation of checkpoint signaling are vital for replication and viability.
  • Checkpoint signaling is actively dampened at lesion sites.
  • Slx4 and Fun30 displace Rad9, leading to local checkpoint attenuation.
  • This attenuation enables Exo1-dependent resection of stalled forks, facilitating homologous recombination and fork stabilization.

Conclusions:

  • Local checkpoint dampening by Slx4 and Fun30 is a critical mechanism for replication completion.
  • This process promotes cell cycle progression and preserves genome stability.
  • Controlled resection of stalled replication forks is essential for preventing degradation and maintaining genomic integrity.

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