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Updated: May 15, 2025

Direct Restart of a Replication Fork Stalled by a Head-On RNA Polymerase
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The PIN1-p38-CtIP signalling axis protects stalled replication forks from deleterious degradation

Francesca Vivalda1, Marco Gatti1, Letizia Manfredi1

  • 1Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.

Nucleic Acids Research
|April 10, 2025
PubMed

Insights

The PIN1-p38-CtIP pathway stabilizes stalled replication forks, crucial for genome stability. This pathway is essential for protecting forks but not for homologous recombination, offering new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genomics

Background:

  • CtIP is vital for DNA double-strand break repair via homologous recombination (HR) and for protecting stalled replication forks.
  • The signaling mechanisms controlling CtIP's distinct roles in fork protection and HR are not fully understood.

Purpose of the Study:

  • To elucidate the upstream signaling pathways regulating CtIP's function in replication fork stabilization versus homologous recombination.
  • To investigate the role of p38α kinase and PIN1 in controlling CtIP activity.

Main Methods:

  • Phosphorylation of CtIP by p38α and subsequent PIN1-mediated isomerization were analyzed.
  • CtIP mutants were used to assess the requirement for phosphorylation and isomerization in fork protection.
  • The impact of PIN1 or p38α inhibition on PARP inhibitor-resistant Brca1-deficient mammary tumor cells was evaluated.

Main Results:

  • Phosphorylation of CtIP by p38α and PIN1 isomerization are essential for replication fork stabilization but not for HR.
  • Cells lacking functional PIN1-p38-CtIP signaling exhibit degradation of stalled forks.
  • A trans-locked CtIP mutant rescued fork protection independently of PIN1-p38α activity.
  • Inhibition of PIN1 or p38α restored chemosensitivity in PARP inhibitor-resistant Brca1-deficient mammary tumor cells.

Conclusions:

  • The PIN1-p38-CtIP signaling pathway is a critical regulator of replication fork integrity.
  • This pathway represents a potential therapeutic target for overcoming resistance to PARP inhibitors in certain cancers.

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