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oai:gredos.usal.es:10366/1551072025-04-30T19:25:52Zcom_10366_3966com_10366_3947com_10366_3946com_10366_3823col_10366_3967

PARP-1 activation after oxidative insult promotes energy stress-dependent phosphorylation of YAP1 and reduces cell viability Martín-Guerrero, Sandra M Casado, Pedro Hijazi Vega, Maruan Rajeeve, Vinothini Plaza-Díaz, Julio Abadía-Molina, Francisco Navascués, Julio Cuadros, Miguel A Cutillas, Pedro R Martín-Oliva, David Oxidative Stress Cell survival [EN]Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that catalyze the transfer of ADP-ribose units from NAD+ to several target proteins involved in cellular stress responses. Using WRL68 (HeLa derivate) cells, we previously showed that PARP-1 activation induced by oxidative stress after H2O2 treatment lead to depletion of cellular NAD+ and ATP, which promoted cell death. In this work, LC-MS/MS-based phosphoproteomics in WRL68 cells showed that the oxidative damage induced by H2O2 increased the phosphorylation of YAP1, a transcriptional co-activator involved in cell survival, and modified the phosphorylation of other proteins involved in transcription. Genetic or pharmacological inhibition of PARP-1 in H2O2-treated cells reduced YAP1 phosphorylation and degradation and increased cell viability. YAP1 silencing abrogated the protective effect of PARP-1 inhibition, indicating that YAP1 is important for the survival of WRL68 cells exposed to oxidative damage. Supplementation of NAD+ also reduced YAP1 phosphorylation, suggesting that the loss of cellular NAD+ caused by PARP-1 activation after oxidative treatment is responsible for the phosphorylation of YAP1. Finally, PARP-1 silencing after oxidative treatment diminished the activation of the metabolic sensor AMPK. Since NAD+ supplementation reduced the phosphorylation of some AMPK substrates, we hypothesized that the loss of cellular NAD+ after PARP-1 activation may induce an energy stress that activates AMPK. In summary, we showed a new crucial role of PARP-1 in the response to oxidative stress in which PARP-1 activation reduced cell viability by promoting the phosphorylation and degradation of YAP1 through a mechanism that involves the depletion of NAD+. 2024-01-31T12:46:59Z 2024-01-31T12:46:59Z 2024-01-31T12:46:59Z 2020-12-11 info:eu-repo/semantics/article Martín-Guerrero, S. M., Casado, P., Hijazi, M., Rajeeve, V., Plaza-Díaz, J., Abadía-Molina, F., ... & Martín-Oliva, D. (2020). PARP-1 activation after oxidative insult promotes energy stress-dependent phosphorylation of YAP1 and reduces cell viability. Biochemical Journal, 477(23), 4491-4513. https://doi.org/10.1042/BCJ20200525 0264-6021 http://hdl.handle.net/10366/155107 10.1042/BCJ20200525 33146386 1470-8728 eng https://doi.org/10.1042/BCJ20200525 info:eu-repo/semantics/openAccess Portland Press