DNA Quadruplex Structure with a Unique Cation Dependency

DNA quadruplex structures provide an additional layer of regulatory control in genome maintenance and gene expression and are widely used in nanotechnology. We report the discovery of an unprecedented tetrastranded structure formed from a native G‐rich DNA sequence originating from the telomeric reg...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2024-02, Vol.63 (7), p.e202313226-n/a
Main Authors: Gajarsky, Martin, Stadlbauer, Petr, Sponer, Jiri, Cucchiarini, Anne, Dobrovolna, Michaela, Brazda, Vaclav, Mergny, Jean‐Louis, Trantirek, Lukas, Lenarcic Zivkovic, Martina
Format: Article
Language:English
Subjects:
Animals
Antiparasitic agents
Base Sequence
Binding sites
Biochemistry, Molecular Biology
Biophysics
Caenorhabditis elegans - genetics
Cations
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA structure
Drug screening
Folding
G-Quadruplexes
Gene expression
Genomes
Humans
Life Sciences
Microbiology and Parasitology
Nanotechnology
NMR spectroscopy
Nucleotide sequence
Parasites
Parasitology
quadruplex
telomere
Telomere - genetics
Telomeres
Therapeutic targets
unique cation dependency
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Summary:DNA quadruplex structures provide an additional layer of regulatory control in genome maintenance and gene expression and are widely used in nanotechnology. We report the discovery of an unprecedented tetrastranded structure formed from a native G‐rich DNA sequence originating from the telomeric region of Caenorhabditis elegans. The structure is defined by multiple properties that distinguish it from all other known DNA quadruplexes. Most notably, the formation of a stable so‐called KNa‐quadruplex (KNaQ) requires concurrent coordination of K+ and Na+ ions at two distinct binding sites. This structure provides novel insight into G‐rich DNA folding under ionic conditions relevant to eukaryotic cell physiology and the structural evolution of telomeric DNA. It highlights the differences between the structural organization of human and nematode telomeric DNA, which should be considered when using C. elegans as a model in telomere biology, particularly in drug screening applications. Additionally, the absence/presence of KNaQ motifs in the host/parasite introduces an intriguing possibility of exploiting the KNaQ fold as a plausible antiparasitic drug target. The structure's unique shape and ion dependency and the possibility of controlling its folding by using low‐molecular‐weight ligands can be used for the design or discovery of novel recognition DNA elements and sensors. A tetrastranded DNA structure, KNa‐quadruplex (KNaQ), is described. KNaQ forms from repetitive DNA sequences that are abundant in (parasitic) worms but extremely rare in humans or livestock. This opens a possibility of exploiting the fold as a plausible antiparasitic drug target. The structure's unique properties distinguish it from all other known DNA quadruplexes and can be used to design novel recognition DNA elements/sensors.
ISSN:1433-7851
1521-3773
1521-3773
DOI:10.1002/anie.202313226