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Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells

DNA is intrinsically dynamic and folds transiently into alternative higher-order structures such as G-quadruplexes (G4s) and three-way DNA junctions (TWJs). G4s and TWJs can be stabilised by small molecules (ligands) that have high chemotherapeutic potential, either as standalone DNA damaging agents...

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Autores principales: Zell, Joanna, Duskova, Katerina, Chouh, Leïla, Bossaert, Madeleine, Chéron, Nicolas, Granzhan, Anton, Britton, Sébastien, Monchaud, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501980/
https://www.ncbi.nlm.nih.gov/pubmed/34551430
http://dx.doi.org/10.1093/nar/gkab796
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author Zell, Joanna
Duskova, Katerina
Chouh, Leïla
Bossaert, Madeleine
Chéron, Nicolas
Granzhan, Anton
Britton, Sébastien
Monchaud, David
author_facet Zell, Joanna
Duskova, Katerina
Chouh, Leïla
Bossaert, Madeleine
Chéron, Nicolas
Granzhan, Anton
Britton, Sébastien
Monchaud, David
author_sort Zell, Joanna
collection PubMed
description DNA is intrinsically dynamic and folds transiently into alternative higher-order structures such as G-quadruplexes (G4s) and three-way DNA junctions (TWJs). G4s and TWJs can be stabilised by small molecules (ligands) that have high chemotherapeutic potential, either as standalone DNA damaging agents or combined in synthetic lethality strategies. While previous approaches have claimed to use ligands that specifically target either G4s or TWJs, we report here on a new approach in which ligands targeting both TWJs and G4s in vitro demonstrate cellular effects distinct from that of G4 ligands, and attributable to TWJ targeting. The DNA binding modes of these new, dual TWJ-/G4-ligands were studied by a panel of in vitro methods and theoretical simulations, and their cellular properties by extensive cell-based assays. We show here that cytotoxic activity of TWJ-/G4-ligands is mitigated by the DNA damage response (DDR) and DNA topoisomerase 2 (TOP2), making them different from typical G4-ligands, and implying a pivotal role of TWJs in cells. We designed and used a clickable ligand, TrisNP-α, to provide unique insights into the TWJ landscape in cells and its modulation upon co-treatments. This wealth of data was exploited to design an efficient synthetic lethality strategy combining dual ligands with clinically relevant DDR inhibitors.
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spelling pubmed-85019802021-10-12 Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells Zell, Joanna Duskova, Katerina Chouh, Leïla Bossaert, Madeleine Chéron, Nicolas Granzhan, Anton Britton, Sébastien Monchaud, David Nucleic Acids Res Chemical Biology and Nucleic Acid Chemistry DNA is intrinsically dynamic and folds transiently into alternative higher-order structures such as G-quadruplexes (G4s) and three-way DNA junctions (TWJs). G4s and TWJs can be stabilised by small molecules (ligands) that have high chemotherapeutic potential, either as standalone DNA damaging agents or combined in synthetic lethality strategies. While previous approaches have claimed to use ligands that specifically target either G4s or TWJs, we report here on a new approach in which ligands targeting both TWJs and G4s in vitro demonstrate cellular effects distinct from that of G4 ligands, and attributable to TWJ targeting. The DNA binding modes of these new, dual TWJ-/G4-ligands were studied by a panel of in vitro methods and theoretical simulations, and their cellular properties by extensive cell-based assays. We show here that cytotoxic activity of TWJ-/G4-ligands is mitigated by the DNA damage response (DDR) and DNA topoisomerase 2 (TOP2), making them different from typical G4-ligands, and implying a pivotal role of TWJs in cells. We designed and used a clickable ligand, TrisNP-α, to provide unique insights into the TWJ landscape in cells and its modulation upon co-treatments. This wealth of data was exploited to design an efficient synthetic lethality strategy combining dual ligands with clinically relevant DDR inhibitors. Oxford University Press 2021-09-22 /pmc/articles/PMC8501980/ /pubmed/34551430 http://dx.doi.org/10.1093/nar/gkab796 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Chemical Biology and Nucleic Acid Chemistry
Zell, Joanna
Duskova, Katerina
Chouh, Leïla
Bossaert, Madeleine
Chéron, Nicolas
Granzhan, Anton
Britton, Sébastien
Monchaud, David
Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells
title Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells
title_full Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells
title_fullStr Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells
title_full_unstemmed Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells
title_short Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells
title_sort dual targeting of higher-order dna structures by azacryptands induces dna junction-mediated dna damage in cancer cells
topic Chemical Biology and Nucleic Acid Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501980/
https://www.ncbi.nlm.nih.gov/pubmed/34551430
http://dx.doi.org/10.1093/nar/gkab796
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