Transcription-associated topoisomerase 2α activity is a major effector of cytotoxicity induced by G-quadruplex ligands
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France, France
- Muséum National d'Histoire Naturelle, CNRS, INSERM, France
- INRAE, UR 875, Genotoul Bioinfo, Castanet-Tolosan, France, France
- INRAE, US 1426, Castanet-Tolosan, France, France
- UMR CNRS 5250, Université Grenoble Alpes, Grenoble 38058, France, France
Abstract
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 2-alpha (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.
Data availability
RNA-seq data from wild-type HAP1 and CXR clones have been deposited on SRA with the project ID PRJNA637883
Article and author information
Author details
Jean-Francois Riou
Funding
Agence Nationale de la Recherche (ANR-17-CE18-0002-01)
- Madeleine Bossaert
- Angélique Pipier
- Linh-Trang Nguyễn
- Patrick Calsou
- Sébastien Britton
- Dennis Gomez
Agence Nationale de la Recherche (ANR-16-CE11-0006-01)
- Angélique Pipier
- Jean-Francois Riou
- Eric Defrancq
- Patrick Calsou
- Sébastien Britton
- Dennis Gomez
CANCEROPOLE GSO (Emergence funding CX-Break"")
- Madeleine Bossaert
- Angélique Pipier
- Linh-Trang Nguyễn
- Patrick Calsou
- Sébastien Britton
- Dennis Gomez
Ligue Contre le Cancer (Equipe Labellisée 2018)
- Madeleine Bossaert
- Angélique Pipier
- Linh-Trang Nguyễn
- Patrick Calsou
- Sébastien Britton
- Dennis Gomez
Agence Nationale de la Recherche (ANR-10-INBS-09)
- Céline Noirot
- Remy-Felix Serre
- Olivier Bouchez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Andrés Aguilera, CABIMER, Universidad de Sevilla, Spain
Version history
- Received: November 25, 2020
- Accepted: June 16, 2021
- Accepted Manuscript published: June 28, 2021 (version 1)
- Version of Record published: July 14, 2021 (version 2)
Copyright
© 2021, Bossaert et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Transcription-associated topoisomerase 2α activity is a major effector of cytotoxicity induced by G-quadruplex ligands
eLife 10:e65184.
https://doi.org/10.7554/eLife.65184
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