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

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 mole...

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Published in:bioRxiv
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: Paper
Language:English
Published: Cold Spring Harbor Laboratory 26.06.2024
Edition:1.1
Subjects:
Molecular Biology
ISSN:2692-8205
Online Access:Get full text
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Summary: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.
ISSN:2692-8205
DOI:10.1101/2024.06.25.600562