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

  1. Madeleine Bossaert
  2. Angélique Pipier
  3. Jean-Francois Riou
  4. Céline Noirot
  5. Linh-Trang Nguyễn
  6. Remy-Felix Serre
  7. Olivier Bouchez
  8. Eric Defrancq
  9. Patrick Calsou
  10. Sébastien Britton
  11. Dennis Gomez  Is a corresponding author
  1. Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France, France
  2. Muséum National d'Histoire Naturelle, CNRS, INSERM, France
  3. INRAE, UR 875, Genotoul Bioinfo, Castanet-Tolosan, France, France
  4. INRAE, US 1426, Castanet-Tolosan, France, France
  5. 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

The following data sets were generated

Article and author information

Author details

  1. Madeleine Bossaert

    Cancer, Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Angélique Pipier

    Cancer, Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8481-2860
  3. Jean-Francois Riou

    Muséum National d'Histoire Naturelle, CNRS, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0055-6506
  4. Céline Noirot

    Unité de Mathématique et Informatique Appliquées, INRAE, UR 875, Genotoul Bioinfo, Castanet-Tolosan, France, Castanet-Tolosan, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Linh-Trang Nguyễn

    Cancer, Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Remy-Felix Serre

    GeT-PlaGe, Genotoul, INRAE, US 1426, Castanet-Tolosan, France, Castanet-Tolosan, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Olivier Bouchez

    GeT-PlaGe, Genotoul,, INRAE, US 1426, Castanet-Tolosan, France, Castanet-Tolosan, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Eric Defrancq

    Département de Chimie Moléculaire, UMR CNRS 5250, Université Grenoble Alpes, Grenoble 38058, France, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Patrick Calsou

    Cancer, Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Sébastien Britton

    Cancer, Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7008-5316
  11. Dennis Gomez

    Cancer, Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France, Toulouse, France
    For correspondence
    dennis.gomez@ipbs.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9942-1451

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

  1. Andrés Aguilera, CABIMER, Universidad de Sevilla, Spain

Publication history

  1. Received: November 25, 2020
  2. Accepted: June 16, 2021
  3. Accepted Manuscript published: June 28, 2021 (version 1)
  4. 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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  1. Madeleine Bossaert
  2. Angélique Pipier
  3. Jean-Francois Riou
  4. Céline Noirot
  5. Linh-Trang Nguyễn
  6. Remy-Felix Serre
  7. Olivier Bouchez
  8. Eric Defrancq
  9. Patrick Calsou
  10. Sébastien Britton
  11. Dennis Gomez
(2021)
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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