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

Abstract Human CtIP plays a critical role in homologous recombination (HR) by promoting the resection of DNA double-strand breaks. Moreover, CtIP maintains genome stability through protecting stalled replication forks from nucleolytic degradation. However, the upstream signalling mechanisms governin...

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Published in:	Nucleic acids research Vol. 53; no. 7
Main Authors:	Vivalda, Francesca, Gatti, Marco, Manfredi, Letizia, Dogan, Hülya, Porro, Antonio, Collotta, Giulio, Ceppi, Ilaria, von Aesch, Christine, van Ackeren, Vanessa, Wild, Sebastian, Steger, Martin, Canovas, Begoña, Cubillos-Rojas, Monica, Riera, Antoni, Cejka, Petr, Nebreda, Angel R, Dibitetto, Diego, Rottenberg, Sven, Sartori, Alessandro A
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 10.04.2025
Subjects:	BRCA1 Protein - genetics Carrier Proteins - genetics Carrier Proteins - metabolism Cell Line, Tumor DNA Breaks, Double-Stranded DNA Replication Endodeoxyribonucleases Genome Integrity, Repair and Humans Mitogen-Activated Protein Kinase 14 - genetics Mitogen-Activated Protein Kinase 14 - metabolism NIMA-Interacting Peptidylprolyl Isomerase - genetics NIMA-Interacting Peptidylprolyl Isomerase - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism p38 Mitogen-Activated Protein Kinases - metabolism Phosphorylation Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Signal Transduction
ISSN:	0305-1048, 1362-4962, 1362-4962
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Summary:	Abstract Human CtIP plays a critical role in homologous recombination (HR) by promoting the resection of DNA double-strand breaks. Moreover, CtIP maintains genome stability through protecting stalled replication forks from nucleolytic degradation. However, the upstream signalling mechanisms governing the molecular switch between these two CtIP-dependent processes remain largely elusive. Here, we show that phosphorylation of CtIP by the p38α stress kinase and subsequent PIN1-mediated CtIP cis-to-trans isomerization is required for fork stabilization but dispensable for HR. We found that stalled forks are degraded in cells expressing non-phosphorylatable CtIP or lacking PIN1–p38α activity, while expression of a CtIP trans-locked mutant overcomes the requirement for PIN1–p38α in fork protection. We further reveal that Brca1-deficient mammary tumour cells that have acquired PARP inhibitor (PARPi) resistance regain chemosensitivity after PIN1 or p38α inhibition. Collectively, our findings identify the PIN1–p38–CtIP signalling pathway as a critical regulator of replication fork integrity. Graphical Abstract Graphical Abstract
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ISSN:	0305-1048 1362-4962 1362-4962
DOI:	10.1093/nar/gkaf278