NDLI: The PIN1-p38-CtIP signaling axis protects stalled replication forks from deleterious degradation

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

Content Provider	bioRxiv
Author	Vivalda, Francesca Gatti, Marco Manfredi, Letizia Dogan, Hülya Porro, Antonio Collotta, Giulio Ceppi, Ilaria Aesch, Christine Von Ackeren, Vanessa Van Wild, Sebastian Steger, Martin Canovas, Begoña Cubillos-rojas, Monica Riera, Antoni Cejka, Petr Angel, R. Nebreda Dibitetto, Diego Rottenberg, Sven Alessandro, A. Sartori
Copyright Year	2024
Abstract	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 signaling 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 tumor cells that have acquired PARPi resistance regain chemosensitivity after PIN1 or p38α inhibition. Collectively, our findings identify the PIN1-p38-CtIP signaling pathway as a critical regulator of replication fork integrity.
Related Links	https://www.biorxiv.org/content/biorxiv/early/2024/06/26/2024.06.25.600562.full.pdf
DOI	10.1101/2024.06.25.600562
Language	English
Publisher	Cold Spring Harbor Laboratory
Publisher Date	2024-06-26
Access Restriction	Open
Rights License	Creative Commons License (Attribution-NonCommercial 4.0 International), CC BY-NC 4.0
Subject Keyword	Molecular Biology
Content Type	Text
Resource Type	Preprint
Subject	Molecular Biology

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