Vivalda, FrancescaFrancescaVivaldaGatti, MarcoMarcoGattiManfredi, LetiziaLetiziaManfrediDoğan, HülyaHülyaDoğanPorro, AntonioAntonioPorroCollotta, GiulioGiulioCollottaCeppi, IlariaIlariaCeppivon Aesch, ChristineChristinevon Aeschvan Ackeren, VanessaVanessavan AckerenWild, SebastianSebastianWildSteger, MartinMartinStegerCanovas, BegoñaBegoñaCanovasCubillos-Rojas, MonicaMonicaCubillos-RojasRiera, AntoniAntoniRieraCejka, PetrPetrCejkaNebreda, Angel RAngel RNebredaDibitetto, DiegoDiegoDibitettoRottenberg, SvenSvenRottenberg0000-0003-2044-9844Sartori, Alessandro AAlessandro ASartori2025-04-282025-04-282025-04-10https://boris-portal.unibe.ch/handle/20.500.12422/209778Human 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.en600 - Technology::610 - Medicine & health500 - Science::590 - Animals (Zoology)article10.48620/875674020763210.1093/nar/gkaf278