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

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.

Références

Titre
Transcription-associated topoisomerase 2α activity is a major effector of cytotoxicity induced by G-quadruplex ligands
Type de publication
Article de revue
Année de publication
2021
Secondary Authors
Aguilera, Andrés
Revue
eLife
Volume
10
Pagination
e65184
Date de publication
06/2021
ISSN
2050-084X
Soumis le 29 juin 2021