Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions Martí, Juan Manuel García Díaz, Ángel Delgado Bellido, Daniel O'Valle Ravassa, Francisco Javier González Flores, Ariannys Oliver Pozo, Francisco Javier Hypoxia PARP-1 PARylation ChIP-seq Tumor microenvironment This work was supported by Junta de Andalucia, project of Excellence from Junta de Andalucia P10-CTS-0662, P12-CTS-383 to FJO, Spanish Ministry of Economy and Competitiveness SAF2012-40011C02-01, SAF2015-70520-R, RTI2018-098968-B-I00, RTICC RD12/0036/0026 and CIBER Cancer ISCIII CB16/12/00421 to FJO. EB1s lab is supported by the Basque Department of Industry, Tourism and Trade (Etortek) and the MINECO (CB16/12/00421) grants. Fundacion Domingo Martinez (call 2019). We would like to acknowledge Laura L´opez for technical assistance; Eduardo Andr´es and Laura Terr´on (Bioinformatic core IPBLN, CSIC) and Pan Hui (Bioinformatic Core, Joslin Diabetes center, Harvard Medical School). Background: The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expression/ activity of HIF-1α correlates with poor prognosis in cancer patients. PARP-1 inhibitors are used in the clinic to treat BRCAness breast/ovarian cancer and have been shown to regulate the hypoxic response; therefore, their use could be expanded. Methods: In this work by integrating molecular/cell biology approaches, genome-wide ChIP-seq, and patient samples, we elucidate the extent to which PARP-1 exerts control over HIF-1-regulated genes. Results: In human melanoma, PARP-1 and HIF-1α expression are strongly associated. In response to a hypoxic challenge poly(ADP-ribose) (PAR) is synthesized, HIF-1α is post-transcriptionally modified (PTM) and stabilized by PARylation at specific K/R residues located at its C-terminus. Using an unbiased ChIP-seq approach we demonstrate that PARP-1 dictates hypoxia-dependent HIF-recruitment to chromatin in a range of HIF-regulated genes while analysis of HIF-binding motifs (RCGTG) reveals a restriction on the recognition of hypoxia responsive elements in the absence of PARP-1. Consequently, the cells are poorly adapted to hypoxia, showing a reduced fitness during hypoxic induction. Conclusions: These data characterize the fine-tuning regulation by PARP-1/PARylation of HIF activation and suggest that PARP inhibitors might have therapeutic potential against cancer types displaying HIF-1α overactivation. 2021-06-14T06:52:08Z 2021-06-14T06:52:08Z 2021-02-01 info:eu-repo/semantics/article Juan Manuel Martí, Angel Garcia-Diaz, Daniel Delgado-Bellido, Francisco O'Valle, Ariannys González-Flores, Onintza Carlevaris, José Manuel Rodríguez-Vargas, Jean Christophe Amé, Françoise Dantzer, George L. King, Klaudia Dziedzic, Edurne Berra, E. de Álava, A.T. Amaral, Ester M. Hammond, F. Javier Oliver, Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions, Redox Biology, Volume 41, 2021, 101885, ISSN 2213-2317, [https://doi.org/10.1016/j.redox.2021.101885] http://hdl.handle.net/10481/69143 10.1016/j.redox.2021.101885 eng http://creativecommons.org/licenses/by-nc-nd/3.0/es/ info:eu-repo/semantics/openAccess Atribución-NoComercial-SinDerivadas 3.0 España Elsevier