Concentration-Dependent Structural Transitions of Human Telomeric DNA Sequences

The 3'-terminal extension of eukaryotic chromosomes are a unique example of functional single-stranded DNA. Human telomeres are constructed of the repeated DNA sequence 5'-d(TTAGGG). Four-repeats of human telomeric DNA have been characterized by high-resolution techniques to be capable of forming at least five distinct monomeric conformations. The predominant solution topology is influenced by solution conditions and the presence of 3'- or 5'-flanking residues. This study extends recently described sequential unfolding mechanisms for human telomeric quadruplexes to eight telomeric DNA sequences that form three unique topologies. Thermal unfolding monitored by circular dichroism is subjected to singular value decomposition to enumarate the number of significant spectral species required to model the unfolding process. Thermal denaturations are found to be best modeled by a four-state sequential mechanism with ΔGave = −8.8 kcal mol−1. The thermal unfolding was also investigated in 50% (v/v) acetonitrile. Under dehydrated conditions, quadruplex thermal denaturations are best modeled by a three-state sequential unfolding mechanism. Dehydrated quadruplexes demonstrate increased thermal stability with ΔGave = −12.7 kcal mol−1. A common spectral intermediate is shared amongst human telomere quadruplex thermal unfolding regardless of starting topology and hydration state. This unfolding intermediate was recently characterized as an ensemble of triple-helical structures for a 22-nt human telomeric quadruplex.

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Thermodynamic characterization of human telomere quadruplex unfolding

Buscaglia

Gray

Chaires

2013

Biopolymers

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Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations

et al. 2015

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DNA G-hairpins are potential key structures participating in folding of human telomeric guanine quadruplexes (GQ). We examined their properties by standard MD simulations starting from the folded state and long T-REMD starting from the unfolded state, accumulating ∼130 μs of atomistic simulations. Antiparallel G-hairpins should spontaneously form in all stages of the folding to support lateral and diagonal loops, with sub-μs scale rearrangements between them. We found no clear predisposition for direct folding into specific GQ topologies with specific syn/anti patterns. Our key prediction stemming from the T-REMD is that an ideal unfolded ensemble of the full GQ sequence populates all 4096 syn/anti combinations of its four G-stretches. The simulations can propose idealized folding pathways but we explain that such few-state pathways may be misleading. In the context of the available experimental data, the simulations strongly suggest that the GQ folding could be best understood by the kinetic partitioning mechanism with a set of deep competing minima on the folding landscape, with only a small fraction of molecules directly folding to the native fold. The landscape should further include non-specific collapse processes where the molecules move via diffusion and consecutive random rare transitions, which could, e.g. structure the propeller loops.

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Light-induced oxidation of the telomeric G4 DNA in complex with Zn(II) tetracarboxymethyl porphyrin

et al. 2016

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Structure-specific ligands are convenient tools for the recognition, targeting or probing of non-canonical DNA structures. Porphyrin derivatives exhibit a preference for interaction with G-quadruplex (G4) structures over canonical duplex DNA and are able to cause photoinducible damage to nucleic acids. Here, we show that Zn(II) 5,10,15,20-tetrakis(N-carboxymethyl-4-pyridinium)porphyrin (ZnP1) interacts with different conformations of the telomeric sequence d(TAGGG(TTAGGG)3) at submicromolar concentrations without any detectible disturbance of the particular fold. Among different folds, potassium (3+1) hybrid G4-structure. reveal the highest affinity to ZnP1. The pattern of guanine oxidation is specific for each telomeric DNA conformation and may serve as an additional tool for probing the G4 topology. The potassium (3+1) and parallel G4 conformations are more susceptible to light-induced oxidation than the sodium G4 conformation or double helix of the telomeric DNA. The major products of the guanine modifications are spiroiminodihydantoin (Sp) and 8-oxoguanine (8-oxoG). ZnP1-induced oxidation of guanines results in the structural rearrangement of parallel and (3+1) G4 conformations yielding an antiparallel-like G4 conformation. The mechanism of the observed light-induced conformational changes is discussed.

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Concentration-Dependent Structural Transitions of Human Telomeric DNA Sequences

Cited by 6 publications

References 55 publications

Thermodynamic characterization of human telomere quadruplex unfolding

Thermodynamic characterization of human telomere quadruplex unfolding

Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations

Light-induced oxidation of the telomeric G4 DNA in complex with Zn(II) tetracarboxymethyl porphyrin

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