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

Sartori, A. A.; Vivalda, F.; Gatti, M.; Manfredi, L.; Dogan, H.; Porro, A.; Collotta, G.; Ceppi, I.; von Aesch, C.; van Ackeren, V.; Wild, S.; Steger, M.; Canovas, B.; Cubillos-Rojas, M.; Riera, A.; Cejka, P.; Nebreda, A. R.; Dibitetto, D.; Rottenberg, S.

doi:10.1101/2024.06.25.600562

bioRxiv · 10.1101/2024.06.25.600562

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

Sartori, A. A.·Vivalda, F.·Gatti, M.·Manfredi, L.·Dogan, H.·Porro, A.·Collotta, G.·Ceppi, I.·von Aesch, C.·van Ackeren, V.·Wild, S.·Steger, M.·Canovas, B.·Cubillos-Rojas, M.·Riera, A.·Cejka, P.·Nebreda, A. R.·Dibitetto, D.·Rottenberg, S.

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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 p38 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-p38 activity, while expression of a CtIP trans-locked mutant overcomes the requirement for PIN1-p38 in fork protection. We further reveal that Brca1-deficient mammary tumor cells that have acquired PARPi resistance regain chemosensitivity after PIN1 or p38 inhibition. Collectively, our findings identify the PIN1-p38-CtIP signaling pathway as a critical regulator of replication fork integrity.

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Sartori, A. A., Vivalda, F., Gatti, M., Manfredi, L., Dogan, H., Porro, A., Collotta, G., Ceppi, I., von Aesch, C., van Ackeren, V., Wild, S., Steger, M., Canovas, B., Cubillos-Rojas, M., Riera, A., Cejka, P., Nebreda, A. R., Dibitetto, D., Rottenberg, S.. 2024-06-26. The PIN1-p38-CtIP signaling axis protects stalled replication forks from deleterious degradation. https://doi.org/10.1101/2024.06.25.600562

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