Transcription-associated topoisomerase 2α (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands

eLife

Eric Defrancq¹  Céline Noirot²  Olivier Bouchez³  Remy-Felix Serre³  Linh-Trang Nguyên⁴  Sébastien Britton⁵  Dennis Gomez⁵  Patrick Calsou⁵  Madeleine Bossaert⁵  Angélique Pipier⁵  Jean-Francois Riou⁶ 

[1] Département de Chimie Moléculaire, UMR CNRS 5250, Université Grenoble Alpes, Grenoble, France;INRAE, UR 875, Unité de Mathématique et Informatique Appliquées, Genotoul Bioinfo, Castanet-Tolosan, France;INRAE, US 1426, GeT-PlaGe, Genotoul, Castanet-Tolosan, France;Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France;Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France;Equipe Labellisée Ligue Contre le Cancer 2018, Toulouse, France;Structure et Instabilité des Génomes, Muséum National d’Histoire Naturelle, CNRS, INSERM, Paris, France;

关键词: G-quadruplex;    CX-5461;    topoisomerase 2;    DNA breaks;    transcription;    Human;   

DOI  :  10.7554/eLife.65184

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY