The PIN1-p38-CtIP signalling axis protects stalled replication forks from deleterious degradation

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.