Reversible DNA i-motif to hairpin switching induced by copper(<scp>ii</scp>) cations

Day, Henry A.; Wright, Elisé P.; Macdonald, Colin; Gates, Andrew J.; Waller, Zoë A. E.

doi:10.1039/c5cc05111h

Cited by 37 publications

(29 citation statements)

References 27 publications

(41 reference statements)

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“…This was a similar characteristic to the duplex and hairpin structures 32 . Several studies have reported the transformation of an i-motif to a hairpin-like structure 7,33 . On the other hand, the CD spectra of c-MYC IM ( Fig.…”

Section: Structural Transformation Of Vegf Im Upon Binding Of Fismentioning

confidence: 99%

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

Takahashi

Bhattacharjee

Ghosh

et al. 2020

Sci Rep

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The relationship of i-motif DNAs with cancer has prompted the development of specific ligands to detect and regulate their formation. Some plant flavonols show unique fluorescence and anti-cancer properties, which suggest the utility of the theranostics approach to cancer therapy related to i-motif DNA. We investigated the effect of the plant flavonol, fisetin (Fis), on the physicochemical property of i-motif DNAs. Binding of Fis to the i-motif from the promoter region of the human vascular endothelial growth factor (VEGF) gene dramatically induced the excited state intramolecular proton transfer (ESIPT) reaction that significantly enhanced the intensity of the tautomer emission band of Fis. This unique response was due to the coincidence of the structural change from i-motif to the hairpin-like structure which is stabilized via putative Watson-Crick base pairs between some guanines within the loop region of the i-motif and cytosines in the structure. As a result, the VEGF i-motif did not act as a replication block in the presence of fis, which indicates the applicability of fis for the regulation of gene expression of VEGF. The fluorescence and biological properties of Fis may be utilised for theranostics applications for cancers related to a specific cancer-related gene, such as VEGF. Besides the canonical right-handed DNA double helix, DNA sequences can adopt non-canonical structures, including G-quadruplexes (G4s) and i-motifs, that are stabilised by non-Watson-Crick base pairing 1. G4 structures are formed from guanine (G)-rich sequences, whereas i-motifs are formed from the cytosine (C)-rich sequences. The i-motif structure consists of two parallel duplexes that intercalate with each other in an antiparallel orientation (Fig. 1A). The parallel duplexes are held together via hydrogen bonding between a neutral cytosine (C) and a protonated cytosine (C +) (Fig. 1B) 2. The formation of an i-motif structure occurs more readily in an acidic condition because protonation of cytosine is required to form a hemiprotonated CC + base pair. However, there is increasing evidence to suggest that the i-motif structures can also form at neutral pH 3,4 and even in the nuclei of living mammalian cells 5,6. The i-motif forming sequences are found in or near the promoter regions of >40% of all human genes, which can regulate the expressions of genes like Bcl2 7,8 and HRAS 9. Furthermore, the i-motif along the cancer-related DNA sequences strongly inhibits DNA replication 10. Therefore, i-motif DNAs are attractive targets for the diagnosis of cancer risk and to treat cancer by the modulation of gene transcription and replication. Considering the use of specific targeted therapy based on specific targeted test (i.e., theranostics) for both diagnosis and therapeutics, some ligands that both emit a fluorescent signal upon binding to a specific i-motif and regulate the transcription or replication of the target gene are required. Currently, no ligands have such dual functions for i-motif DNAs. Flavonols and other related compounds o...

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Section: Structural Transformation Of Vegf Im Upon Binding Of Fismentioning

confidence: 99%

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

Takahashi

Bhattacharjee

Ghosh

et al. 2020

Sci Rep

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“…In addition to (C:H:C) + pairs, recent experimental results demonstrate that a series of metal cations (M z + ) stabilize i‐motifs in terms of (C:M:C) z + pairs, notably even at neutral pH values . In contrast to stabilizing ions like Ag + or Cu + , it was further reported that cations like Na + , Cu 2+ , and Li + destabilize the i‐motif . In this context, pronounced interactions between Cu 2+ ions and DNA were reported, which are of biological importance with regard to the fact, that cancer cells usually show elevated copper levels .…”

Section: Introductionmentioning

confidence: 99%

On the nature of ion‐stabilized cytosine pairs in DNA i‐motifs: The importance of charge transfer processes

Kohagen

Uhlig

Smiatek

2019

Int J of Quantum Chemistry

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Recent experimental results indicate that the stability of non‐Watson‐Crick DNA i‐motif structures can be influenced by the presence of various metal cations. Whereas Au+, Cu+, and Ag+ are stabilizing agents, alkali metal ions like Na+ or Li+ are known to destabilize the i‐motif. In terms of reduced ion‐cytosine complexes, we rationalize the experimental observations with the help of standard and conceptual density functional theory (DFT) calculations. Our results highlight the importance of coordinating electrostatic bonds with partially covalent character for the stability of the ion‐cytosine complex. The occurrence of these bonds can be mainly attributed to charge transfer processes between two cytosines and the transition metal ions, which can be either explained by frontier molecular orbital theory in combination with a bond critical point analysis, or by the concept of chemical reactivity indices within a conceptual DFT approach. The results of our calculations establish a consistent theoretical framework to understand the experimentally observed behavior, and are also important in order to achieve more detailed insights into nucleobase pairing mechanisms in general.

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“…There is increasing evidence that these types of structures provide opportunities to regulate DNA metabolism in bacteria [51,[75][76][77]. The genome of the bacterium Paracoccus denitrificans PD1222 has a relatively high G + C content (∼67%) and a range of biophysical, molecular, and microbiological studies show that targeting of four-stranded structures can be controlled under cellular conditions, allowing regulation of expression of some genes [48,[78][79][80][81].…”

Section: Biochemical and Cellular Impacts Of Simple Repeat Sequences mentioning

confidence: 99%

Structures and stability of simple DNA repeats from bacteria

Brázda

Fojta

Bowater

2020

Biochemical Journal

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DNA is a fundamentally important molecule for all cellular organisms due to its biological role as the store of hereditary, genetic information. On the one hand, genomic DNA is very stable, both in chemical and biological contexts, and this assists its genetic functions. On the other hand, it is also a dynamic molecule, and constant changes in its structure and sequence drive many biological processes, including adaptation and evolution of organisms. DNA genomes contain significant amounts of repetitive sequences, which have divergent functions in the complex processes that involve DNA, including replication, recombination, repair, and transcription. Through their involvement in these processes, repetitive DNA sequences influence the genetic instability and evolution of DNA molecules and they are located non-randomly in all genomes. Mechanisms that influence such genetic instability have been studied in many organisms, including within human genomes where they are linked to various human diseases. Here, we review our understanding of short, simple DNA repeats across a diverse range of bacteria, comparing the prevalence of repetitive DNA sequences in different genomes. We describe the range of DNA structures that have been observed in such repeats, focusing on their propensity to form local, non-B-DNA structures. Finally, we discuss the biological significance of such unusual DNA structures and relate this to studies where the impacts of DNA metabolism on genetic stability are linked to human diseases. Overall, we show that simple DNA repeats in bacteria serve as excellent and tractable experimental models for biochemical studies of their cellular functions and influences.

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Reversible DNA i-motif to hairpin switching induced by copper(ii) cations

Abstract: i-Motif forming DNA sequences have previously been used for many different nanotechnological applications, but all have used changes in pH to fold the DNA. Here it is shown that Cu(ii) cations can be used to re-fold i-motifs into hairpin structures, without changing the pH.

Cited by 37 publications

References 27 publications

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

On the nature of ion‐stabilized cytosine pairs in DNA i‐motifs: The importance of charge transfer processes

Structures and stability of simple DNA repeats from bacteria

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