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

2021; eLife Sciences Publications Ltd; Volume: 10; Linguagem: Inglês

10.7554/elife.65184

2050-084X

Madeleine Bossaert, Angélique Pipier, Jean‐François Riou, Céline Noirot, Linh-Trang Nguyên, Rémy-Félix Serre, Olivier Bouchez, Éric Defrancq, Patrick Calsou, Sébastien Britton, Dennis Gómez,

Advanced biosensing and bioanalysis techniques

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.