Discovery of “folded DNA” structures in human cells: Potential drug targets

Raffa, Robert B.; Pergolizzi, Joseph V.; Taylor, Robert; Ossipov, Michael H.

doi:10.1111/jcpt.12758

Cited by 2 publications

(2 citation statements)

References 42 publications

(65 reference statements)

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“…Recently, G-quadruplexes have been revealed in human cells using an antibody and small molecules (6–8) and shown to play important roles in numerous processes such as DNA replication, recombination, transcription, translation and telomere maintenance (9–17). Therefore, these findings greatly boosted the attention toward G-quadruplexes as attractive therapeutic targets for anti-cancer drug design (8,18,19). In this light, the structural details are required to develop highly specific ligands capable of discriminating the diverse human telomeric G-quadruplex topologies/structures.…”

Section: Introductionmentioning

confidence: 99%

The crystal structure of an antiparallel chair-type G-quadruplex formed by Bromo-substituted human telomeric DNA

Geng

Liu

Zhou

et al. 2019

Nucleic Acids Research

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Human telomeric guanine-rich DNA, which could adopt different G-quadruplex structures, plays important roles in protecting the cell from recombination and degradation. Although many of these structures were determined, the chair-type G-quadruplex structure remains elusive. Here, we present a crystal structure of the G-quadruplex composed of the human telomeric sequence d[GGGTTAGG 8 GTTAGGGTTAGG 20 G] with two dG to 8Br-dG substitutions at positions 8 and 20 with syn conformation in the K + solution. It forms a novel three-layer chair-type G-quadruplex with two linking trinucleotide loops. Particularly, T5 and T17 are coplanar with two water molecules stacking on the G-tetrad layer in a sandwich-like mode through a coordinating K + ion and an A6•A18 base pair. While a twisted Hoogsteen A12•T10 base pair caps on the top of G-tetrad core. The three linking TTA loops are edgewise and each DNA strand has two antiparallel adjacent strands. Our findings contribute to a deeper understanding and highlight the unique roles of loop and water molecule in the folding of the G-quadruplex.

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Section: Introductionmentioning

confidence: 99%

The crystal structure of an antiparallel chair-type G-quadruplex formed by Bromo-substituted human telomeric DNA

Geng

Liu

Zhou

et al. 2019

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…Therefore, these findings made G-quadruplexes attractive therapeutic targets for anti-disease/virus drug design (Hansel-Hertsch et al 2017;Neidle 2012;Raffa et al 2018). To date, thousands of small compounds have been reported to bind with G-quadruplexes through stacking with the terminal Gtetrad layer typified by the structure of the bimolecular human telomeric quadruplex, d [TAGGGTTAGGGT] 2 , in complex with the anti-cancer drug BRACO-19 (Campbell et al 2008).…”

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confidence: 99%

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

et al. 2019

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Discovery of “folded DNA” structures in human cells: Potential drug targets

Abstract: The newly identified "folded DNA" structures ("I-motifs" and "G-quadruplexes") could represent novel drug-discovery targets, most likely for cancer.

Cited by 2 publications

References 42 publications

The crystal structure of an antiparallel chair-type G-quadruplex formed by Bromo-substituted human telomeric DNA

The crystal structure of an antiparallel chair-type G-quadruplex formed by Bromo-substituted human telomeric DNA

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

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