topoisomerase 2 alpha
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eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Madeleine Bossaert ◽  
Angélique Pipier ◽  
Jean-Francois Riou ◽  
Céline Noirot ◽  
Linh-Trang Nguyễn ◽  
...  

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.


Author(s):  
A. Pipier ◽  
M. Bossaert ◽  
J.F. Riou ◽  
C. Noirot ◽  
L-T. Nguyễn ◽  
...  

AbstractG-quadruplexes (G4), non-canonical DNA structures, are involved in several essential processes. Stabilization of G4 structures by small compounds (G4 ligands) affects almost all DNA transactions, including telomere maintenance and genomic stability. Here, thanks to a powerful and unbiased genetic approach, we identify topoisomerase 2-alpha (TOP2A) as the main effector of cell cytotoxicity induced by CX5461, a G4 ligand currently undergoing phase I/II clinical trials. This approach also allowed to identify new point mutations affecting TOP2A activity without compromising cell viability. Moreover, based on cross-resistance studies and siRNA-based protein depletion we report that TOP2A plays a major role in cell cytotoxicity induced by two unrelated clastogenic G4 ligands, CX5461 and pyridostatin (PDS). We also report that cytotoxic effects induced by both compounds are associated with topoisomerase 2-mediated DNA breaks production. Finally, we show that TOP2-mediated DNA breaks production is strongly associated with RNA Pol II-dependent transcription and is countered by topoisomerase 1 (TOP1). Altogether our results indicate that clastogenic G4 ligands act as DNA structure-driven TOP2-poisons at transcribed regions bearing G-quadruplex structures.


PLoS ONE ◽  
2015 ◽  
Vol 10 (11) ◽  
pp. e0142327 ◽  
Author(s):  
J. L. Schaefer-Klein ◽  
Stephen J. Murphy ◽  
Sarah H. Johnson ◽  
George Vasmatzis ◽  
Irina V. Kovtun

2014 ◽  
Vol pii: AOP_14_065 ◽  
Author(s):  
Małgorzata Trofimiuk-Müldner ◽  
Agata Bałdys-Waligórska ◽  
Grzegorz Sokołowski ◽  
Dariusz Adamek ◽  
Alicja Hubalewska-Dydejczyk ◽  
...  

2014 ◽  
Vol 116 (5) ◽  
pp. 740-746 ◽  
Author(s):  
Ivana Mrklić ◽  
Giulio Cesare Spagnoli ◽  
Antonio Juretić ◽  
Zenon Pogorelić ◽  
Snježana Tomić

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