Martí, Juan ManuelGarcia-Diaz, AngelDelgado-Bellido, DanielO'Valle, FranciscoGonzález-Flores, AriannysCarlevaris, OnintzaRodríguez-Vargas, José ManuelAmé, Jean ChristopheDantzer, FrançoiseKing, George L.Dziedzic, KlaudiaBerra, Edurnede Álava, E.Amaral, A. T.Hammond, Ester M.Oliver, F. Javier2022-11-082022-11-082021-02-01Martí JM, Garcia-Diaz A, Delgado-Bellido D, O'Valle F, González-Flores A, Carlevaris O, et al. Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions. Redox Biol. 2021 May;41:101885http://hdl.handle.net/10668/4345Background: The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expres sion/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 over activationenAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/HypoxiaPARP-1PARylationChIP-seqTumor microenvironmentHipoxiaInhibidores de poli(ADP-Ribosa) polimerasasPoli ADP ribosilaciónSecuenciación de inmunoprecipitación de cromatinaMicroambiente tumoralMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Respiration::Cell HypoxiaMedical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cell Nucleus::Cell Nucleus Structures::Intranuclear Space::Chromosomes::Chromosome Structures::ChromatinMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Breast NeoplasmsPoly(ADP-ribose) Polymerase InhibitorsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Vesicular Transport Proteins::Coat Protein Complex I::ADP-Ribosylation Factor 1Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription FactorsMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian NeoplasmsMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Purines::Purine Nucleotides::Adenine Nucleotides::Adenosine Diphosphate::Adenosine Diphosphate Sugarsresearch article33581682open access10.1016/j.redox.2021.1018852213-2317PMC7878192