G-quadruplex structures formed by human telomeric DNA and C9orf72 hexanucleotide repeats

Liu, Changdong; Geng, Yanyan; Miao, Haitao; Xiao, Shi; You, Yingying; Xu, Naining; Zhou, Bo; Zhu, Guang

doi:10.1007/s12551-019-00545-y

Cited by 10 publications

(5 citation statements)

References 52 publications

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“…Several distinct intramolecular G4 structures that formed by telomeric oligonucleotides have been reported. These structures contain 21-mer telomeric core sequence d[GGG(TTAGGG) 3 ] in the center, and the G4 structures that formed depend on the flanking sequences and available cations [25]. In the presence of Na + , the wild-type of 22-mer telomeric oligonucleotide d[AGGG(TTAGGG) 3 ] (A-Tel21) formed an intramolecular antiparallel basket-type G4 structure (Figure 1a) [26].…”

Section: Introductionmentioning

confidence: 99%

Thermal Stability Changes in Telomeric G-Quadruplex Structures Due to N6-Methyladenine Modification

Wada

Yoshida

2021

Epigenomes

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N6-methyladenosine modification (m6dA) has recently been identified in eukaryote genomic DNA. The methylation destabilizes the duplex structure when the adenine forms a Watson–Crick base pair, whereas the methylation on a terminal unpaired adenine stabilizes the duplex structure by increasing the stacking interaction. In this study, the effects of m6dA modification on the thermal stability of four distinct telomeric G-quadruplex (G4) structures were investigated. The m6dA-modified telomeric oligonucleotide d[AGGG(TTAGGG)3] that forms a basket-type G4 in Na+, d[(TTAGGG)4TT] that forms a hybrid-type G4 in K+ (Form-2), d[AAAGGG(TTAGGG)3AA] that forms a hybrid-type G4 in K+ (Form-1), and d[GGG(TTAGGG)3T] that forms a basket-type G4 with two G-tetrads in K+ (Form-3) were analyzed. Circular dichroism melting analysis demonstrated that (1) A7- and A19-methylation destabilized the basket-type G4 structure that formed in Na+, whereas A13-methylation stabilized the structure; (2) A15-methylation stabilized the Form-2 G4 structure; (3) A15- and A21-methylations stabilized the Form-1 G4 structure; and (4) A12-methylation stabilized the Form-3 G4 structure. These results suggest that m6dA modifications may affect the thermal stability of human telomeric G4 structures in regulating the biological functions.

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Section: Introductionmentioning

confidence: 99%

Thermal Stability Changes in Telomeric G-Quadruplex Structures Due to N6-Methyladenine Modification

Wada

Yoshida

2021

Epigenomes

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“…For example, the conformation of human telomeric variant htel21 _T18 (d[(GGGTTA) 2 GGGTTTGGG]) G4 is a chair type, whereas human telomeric htel23 (d[TA(GGGTTA) 3 GGG]) G4 is a hybrid type. 29 , 30 Nonetheless, 1D 1 H NMR spectra showed no apparent binding between htel21 _T18 G4 ( Figure S30A ) and cA (1:10). Titration of cA (1:10) did not cause any chemical shift changes on the spectra of htel23 _hybrid G4 ( Figure S30B ) or c-kit G4, a parallel form adopted by the c-kit oncogene ( Figure S30C ), 31 suggesting no bindings between cA and htel23 _hybrid G4, or cA and c-kit G4.…”

Section: Resultsmentioning

confidence: 99%

Selective C9orf72 G-Quadruplex-Binding Small Molecules Ameliorate Pathological Signatures of ALS/FTD Models

Cheng

Liu

et al. 2022

J. Med. Chem.

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The G-quadruplex (G4) forming C9orf72 GGGGCC (G4C2) expanded hexanucleotide repeat (EHR) is the predominant genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Developing selective G4-binding ligands is challenging due to the conformational polymorphism and similarity of G4 structures. We identified three first-in-class marine natural products, chrexanthomycin A (cA), chrexanthomycin B (cB), and chrexanthomycin C (cC), with remarkable bioactivities. Thereinto, cA shows the highest permeability and lowest cytotoxicity to live cells. NMR titration experiments and in silico analysis demonstrate that cA, cB, and cC selectively bind to DNA and RNA G4C2 G4s. Notably, cA and cC dramatically reduce G4C2 EHR-caused cell death, diminish G4C2 RNA foci in (G4C2)29-expressing Neuro2a cells, and significantly eliminate ROS in HT22 cells. In (G4C2)29-expressing Drosophila, cA and cC significantly rescue eye degeneration and improve locomotor deficits. Overall, our findings reveal that cA and cC are potential therapeutic agents deserving further clinical study.

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“…The concentrations of DNA and hemin as well as Aβ 1–40 applied in our study suggest an influence of DNAzymes in pathological states such as AD. Additionally, it was shown over the past years that G-quadruplexes are involved in human neurodegenerative diseases indicating their physiological relevance. − Because it was shown that intracellular G-quadruplexes exist, ,, the complex formation with hemin is possible as well as the oxidation of l -tyrosine and of the Aβ 1–40 peptide. Furthermore, it was shown by Rangan et al in 2001 that even in vivo porphyrins can interact with G-quadruplex structures in human cells .…”

Section: Discussionmentioning

confidence: 99%

DNAzymes as Catalysts for l-Tyrosine and Amyloid β Oxidation

et al. 2020

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Single-stranded deoxyribonucleic acids have an enormous potential for catalysis by applying tailored sequences of nucleotides for individual reaction conditions and substrates. If such a sequence is guanine-rich, it may arrange into a three-dimensional structure called G-quadruplex and give rise to a catalytically active DNA molecule, a DNAzyme, upon addition of hemin. Here, we present a DNAzyme-mediated reaction, which is the oxidation of l-tyrosine toward dityrosine by hydrogen peroxide. With an optimal stoichiometry between DNA and hemin of 1:10, we report an activity of 101.2 ± 3.5 μUnits (μU) of the artificial DNAzyme Dz-00 compared to 33.0 ± 1.8 μU of free hemin. Exemplarily, DNAzymes may take part in neurodegeneration caused by amyloid beta (Aβ) aggregation due to l-tyrosine oxidation. We show that the natural, human genome-derived DNAzyme In1-sp is able to oxidize Aβ peptides with a 4.6% higher yield and a 33.3% higher velocity of the reaction compared to free hemin. As the artificial DNAzyme Dz-00 is even able to catalyze Aβ peptide oxidation with a 64.2% higher yield and 337.1% higher velocity, an in-depth screening of human genome-derived DNAzymes may identify further candidates with similarly high catalytic activity in Aβ peptide oxidation.

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G-quadruplex structures formed by human telomeric DNA and C9orf72 hexanucleotide repeats

Cited by 10 publications

References 52 publications

Thermal Stability Changes in Telomeric G-Quadruplex Structures Due to N6-Methyladenine Modification

Thermal Stability Changes in Telomeric G-Quadruplex Structures Due to N6-Methyladenine Modification

Selective C9orf72 G-Quadruplex-Binding Small Molecules Ameliorate Pathological Signatures of ALS/FTD Models

DNAzymes as Catalysts for l-Tyrosine and Amyloid β Oxidation

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