Abstract
The Watson–Crick double helix is only one of the conformations available to genomic DNA. Under physiological conditions, guanine-rich and cytosine-rich tracts fold into G-quadruplexes (G4) and i-motifs (iM) higher-order assemblies stabilised by Hoogsteen-paired guanine tetrads and hemiprotonated cytosine·cytosine base pairs, respectively.1,2 As supramolecular architectures, these structures present recognition surfaces chemically distinct from duplex DNA.1-4
This presentation traces our programme's efforts to selectively recognise, distinguish, and perturb these structures both in vitro and within a cellular context. By combining structure-specific antibodies with rationally designed small-molecule ligands we have demonstrated the interdependency of these structures, the ability to shift their conformational equilibrium and their roles in regulating important processes such as gene expression and cellular transitions.3-5
References
1. Irving, K. et al., Biochimie 198, 33 (2022);
2. Kretzmann, J. A. et al., NAR Cancer 3, zcab048. doi:10.1093/narcan/zcab048 (2021);
3. Ou, A. et al., Nucleic Acids Res. 48, 5766 (2020);
4. Lawler, N., et al., Chemical Science 14, 7681-7687 (2023);
5. King, J. J. et al., bioRxiv 2023.08.21.554220; doi: https://doi.org/10.1101/2023.08.21.554220