Transcription-associated topoisomerase 2α (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands
| Autor: | Olivier Bouchez, Patrick Calsou, Madeleine Bossaert, Linh-Trang Nguyên, Sébastien Britton, Jean-François Riou, Dennis Gomez, Angélique Pipier, Céline Noirot, Eric Defrancq, Remy-Felix Serre |
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| Přispěvatelé: | Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
[SDV]Life Sciences [q-bio]
chemistry.chemical_compound 0302 clinical medicine Transcription (biology) Gene expression CX-5461 DNA Breaks Double-Stranded RNA-Seq Biology (General) Cytotoxicity Picolinic Acids Poly-ADP-Ribose Binding Proteins Cancer Biology 0303 health sciences biology G-quadruplex Effector General Neuroscience General Medicine Chromosomes and Gene Expression Small molecule topoisomerase 2 Biochemistry DNA Topoisomerases Type I 030220 oncology & carcinogenesis Aminoquinolines Medicine RNA Interference transcription Research Article Human QH301-705.5 Cell Survival Science Antineoplastic Agents Polymorphism Single Nucleotide General Biochemistry Genetics and Molecular Biology Gene Expression Regulation Enzymologic Cell Line Colony-Forming Units Assay 03 medical and health sciences Humans DNA breaks Benzothiazoles Naphthyridines 030304 developmental biology Cell Proliferation General Immunology and Microbiology Topoisomerase G-Quadruplexes DNA Topoisomerases Type II chemistry biology.protein DNA |
| Zdroj: | eLife eLife, eLife Sciences Publication, 2021, 10, ⟨10.7554/eLife.65184⟩ eLife, Vol 10 (2021) |
| ISSN: | 2050-084X |
| Popis: | International audience; G-quadruplexes (G4) are non-canonical DNA structures found in the genome of most species including human. Small molecules stabilizing these structures, called G4 ligands, have been identified and, for some of them, shown to induce cytotoxic DNA double-strand breaks. Through the use of an unbiased genetic approach, we identify here topoisomerase 2α (TOP2A) as a major effector of cytotoxicity induced by two clastogenic G4 ligands, pyridostatin and CX-5461, the latter molecule currently undergoing phase I/II clinical trials in oncology. We show that both TOP2 activity and transcription account for DNA break production following G4 ligand treatments. In contrast, clastogenic activity of these G4 ligands is countered by topoisomerase 1 (TOP1), which limits co-transcriptional G4 formation, and by factors promoting transcriptional elongation. Altogether our results support that clastogenic G4 ligands act as DNA structure-driven TOP2 poisons at transcribed regions bearing G4 structures. |
| Databáze: | OpenAIRE |
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