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Targeting DNA Junctions with Small Molecules for Therapeutic Applications in Oncology

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Handbook of Chemical Biology of Nucleic Acids

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Abstract

DNA junctions exist at the branch point of three or four DNA duplexes (dsDNA or B DNA) in hairpin and cruciform structures. These structures occur when repeated dsDNA sequences open up to expose single-stranded DNA (ssDNA), which then folds upon itself to form an intramolecular hairpin. Junctions are thus formed during DNA transactions, i.e., when the dsDNA is being replicated, transcribed, or repaired. Three-way junctions (TWJs) and four-way junctions (FWJs) can encapsulate small molecules, termed ligands, which stabilize the non-B DNA structural motif. In vitro assays employ this stabilization effect to identify junction-binding small molecules. TWJ-binding molecules have C3 symmetry, are approximately 10 Å in diameter, and contain aromatic and positively charged chemical groups; FWJ-binding ligands are often larger with similar chemical motifs and C2 symmetry. We describe here the discovery of junction-binding molecules, culminating in those which show exceptional in vitro binding and promising in cellulo properties. Ligands able to stabilize DNA junctions in cells hinder DNA transactions and thus induce a DNA damage response (DDR), leading to cytotoxicity. This approach is cancer-selective as cancer cells are particularly sensitive to DNA damage due to their impaired DDR mechanisms. Recently, these ligands were incorporated in synthetic lethality strategies, demonstrating the enormous progress that the field of junction targeting has made in only 30 years, which should inspire chemical biologists in the pursuit of more specific ligands and techniques to characterize their molecular mechanism.

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Authors and Affiliations

  1. Institut de Chimie Moléculaire de l’Université de Bourgogne, ICMUB CNRS, Dijon, France

    Joanna Zell & David Monchaud

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  1. Joanna Zell
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  2. David Monchaud
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Correspondence to David Monchaud .

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  1. Frontier Institute for Biomolecular Engineering Research (FIBER), Konan University, Kobe, Japan

    Naoki Sugimoto

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  1. Chemistry, CNRS, Paris, France

    Marie-Paule Teulade-Fichou

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Zell, J., Monchaud, D. (2022). Targeting DNA Junctions with Small Molecules for Therapeutic Applications in Oncology. In: Sugimoto, N. (eds) Handbook of Chemical Biology of Nucleic Acids. Springer, Singapore. https://doi.org/10.1007/978-981-16-1313-5_37-1

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  • DOI: https://doi.org/10.1007/978-981-16-1313-5_37-1

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