BMPQ-1 binds selectively to (3+1) hybrid topologies in human telomeric G-quadruplex multimers

Gao, Chao; Liu, Zhu; Hou, Haitao; Ding, Jiajia; Chen, Xin; Xie, Congbao; Song, Zibing; Hu, Zhe; Feng, Mingqian; Mohamed, Hany I.; Xu, Shicheng; Parkinson, Gary N.; Haider, Shozeb; Wei, Dengguo

doi:10.1093/nar/gkaa870

Cited by 22 publications

(17 citation statements)

References 62 publications

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“…Indeed, during the drafting of this manuscript Gao et al. have demonstrated that a small molecule targeting the wild-type Tel48 can shift the distribution of conformations to favor a more compact, likely stacked, conformation ( 96 )—a transition that would directly affect persistence length. It is well established that telomere G-quadruplex interacting small molecules are able to displace shelterin components, uncap the telomeres, and ultimately, inhibit telomerase in vitro and in vivo ( 14 , 97 ).…”

Section: Discussionmentioning

confidence: 99%

The solution structures of higher-order human telomere G-quadruplex multimers

Monsen

Chakravarthy

Dean

et al. 2021

Nucleic Acids Research

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Human telomeres contain the repeat DNA sequence 5′-d(TTAGGG), with duplex regions that are several kilobases long terminating in a 3′ single-stranded overhang. The structure of the single-stranded overhang is not known with certainty, with disparate models proposed in the literature. We report here the results of an integrated structural biology approach that combines small-angle X-ray scattering, circular dichroism (CD), analytical ultracentrifugation, size-exclusion column chromatography and molecular dynamics simulations that provide the most detailed characterization to date of the structure of the telomeric overhang. We find that the single-stranded sequences 5′-d(TTAGGG)n, with n = 8, 12 and 16, fold into multimeric structures containing the maximal number (2, 3 and 4, respectively) of contiguous G4 units with no long gaps between units. The G4 units are a mixture of hybrid-1 and hybrid-2 conformers. In the multimeric structures, G4 units interact, at least transiently, at the interfaces between units to produce distinctive CD signatures. Global fitting of our hydrodynamic and scattering data to a worm-like chain (WLC) model indicates that these multimeric G4 structures are semi-flexible, with a persistence length of ∼34 Å. Investigations of its flexibility using MD simulations reveal stacking, unstacking, and coiling movements, which yield unique sites for drug targeting.

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Section: Discussionmentioning

confidence: 99%

The solution structures of higher-order human telomere G-quadruplex multimers

Monsen

Chakravarthy

Dean

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…Indeed, during the drafting of this manuscript Gao et al . have demonstrated that a small molecule targeting the wild-type Tel48 can shift the distribution of conformations to favor a more compact, likely stacked, conformation(87)—a transition that would directly affect persistence length. It is well established that telomere G-quadruplex interacting small molecules are able to displace shelterin components, uncap the telomeres, and ultimately, inhibit telomerase in vitro and in vivo (14,88).…”

Section: Discussionmentioning

confidence: 99%

The solution structures of higher-order human telomere G-quadruplex multimers

Monsen

Chakravarthy

Dean

et al. 2020

Preprint

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Human telomeres contain the repeat DNA sequence 5’(TTAGGG), with duplex regions that are several kilobases long terminating in a 3’ single-stranded overhang. The structure of the single-stranded overhang is not known with certainty, with disparate modes proposed in the literature. We report here the results of an integrated structural biology approach that combines small-angle X-ray scattering, circular dichroism (CD), analytical ultracentrifugation, size-exclusion column chromatography and molecular dynamics simulations that provide the most detailed characterization to date of the structure of the telomeric overhang. We find that the single-stranded sequences 5’(TTAGGG)n, with n=8, 12, and 16, fold into multimeric structures containing the maximal number (2, 3, and 4, respectively) of contiguous G4 units with no long gaps between units. The G4 units are a mixture of hybrid-1 and hybrid-2 conformers. In the multimeric structures, G4 units interact, at least transiently, at the interfaces between units to produce distinctive CD signatures. Global fitting of our hydrodynamic and scattering data to a worm-like chain (WLC) model indicates that these multimeric G4 structures are semi-flexible, with a persistence length of about 34 Å. Investigations of its flexibility using MD simulations reveal stacking, unstacking, and coiling movements, which yield unique sites for drug targeting.

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“…BMPQ-1 can induce the formation of telomere G4, causing telomere dysfunction and DNA damage response, followed by cell senescence and apoptosis. The BMPQ-1 also showed good tumor-suppressing effects in lung, liver, and gastric cancer cells and human colon adenocarcinoma xenograft mouse models, even better than of the classical G4 ligand BRACO19 [ 68 ]. In traditional Chinese medicine, many natural compounds have been found to have the ability to stabilize G4 in telomeres and hTERT promoter, and the modified derivatives of these natural products have stronger effects.…”

Section: Small Molecules Targeting G4s In Telomeres and Htert Promotermentioning

confidence: 99%

Research Progress on G-Quadruplexes in Human Telomeres and Human Telomerase Reverse Transcriptase (hTERT) Promoter

Lin

Zhao

et al. 2022

Oxidative Medicine and Cellular Longevity

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The upregulation telomerase activity is observed in over 85-90% of human cancers and provides an attractive target for cancer therapies. The high guanine content in the telomere DNA sequences and the hTERT promoter can form G-quadruplexes (G4s). Small molecules targeting G4s in telomeres and hTERT promoter could stabilize the G4s and inhibit hTERT expression and telomere extension. Several G4 ligands have shown inhibitory effects in cancer cells and xenograft mouse models, indicating these ligands have a potential for cancer therapies. The current review article describes the concept of the telomere, telomerase, and G4s. Moreover, the regulation of telomerase and G4s in telomeres and hTERT promoter is discussed as well. The summary of the small molecules targeting G4s in telomeric DNA sequences and the hTERT promoter will also be shown.

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BMPQ-1 binds selectively to (3+1) hybrid topologies in human telomeric G-quadruplex multimers

Cited by 22 publications

References 62 publications

The solution structures of higher-order human telomere G-quadruplex multimers

The solution structures of higher-order human telomere G-quadruplex multimers

The solution structures of higher-order human telomere G-quadruplex multimers

Research Progress on G-Quadruplexes in Human Telomeres and Human Telomerase Reverse Transcriptase (hTERT) Promoter

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