Effect of RNA sequence context and stereochemistry on G-quadruplex-RHAU53 interaction

Mou, Xi; Kwok, Chun Kit

doi:10.1016/j.bbrc.2020.09.045

Cited by 4 publications

(7 citation statements)

References 15 publications

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“…14,44,45 DHX36 53−105specific motif (DSM) localized in the N-terminal portion is essential in G4 recognition, 58 and several factors like the number of G-tracts, stereochemistry and loop size have been shown to alter binding affinity. 59 MST studies have shown that MP1 and MP2 interact with the N-terminal region of DHX36 53−105 in a comparable nanomolar range to previously reported DNA G4s structures (Figure 7A). 14,58 The difference in binding affinity between MP1 and MP2 could be explained by the difference in loop size and distribution; while MP1 has a smaller and most equally distributed loop, MP2 has a sizeable central loop and only one nucleotide in the side loops.…”

Section: Biophysical Characterization Is Consistent With Mp1 and Mp2supporting

confidence: 79%

Mapping and characterization of G‐quadruplexes in monkeypox genomes

Pereira

Gemmill

Siddiqui

et al. 2023

Journal of Medical Virology

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Monkeypox virus (MPXV) is a double-stranded DNA virus from the family Poxviridae, which is endemic in West and Central Africa. Various human outbreaks occurred in the 1980s, resulting from a cessation of smallpox vaccination. Recently, MPXV cases have reemerged in non-endemic nations, and the 2022 outbreak has been declared a public health emergency. Treatment optionsare limited, and many countries lack the infrastructure to provide symptomatic treatments. The development of cost-effective antivirals could ease severe health outcomes. G-quadruplexes have been a target of interest in treating viral infections with different chemicals. In the present work, a genomic-scale mapping of different MPXV isolates highlighted two conserved putative quadruplex-forming sequences MPXV-exclusive in 590 isolates.Subsequently, we assessed the G-quadruplex formation using circular dichroism spectroscopy and solution small-angle X-ray scattering. Furthermore, biochemical assays indicated the ability of MPXV quadruplexes to be recognized by two specific G4-binding partners-Thioflavin T and DHX36. Additionally, our work also suggests that a quadruplex binding small-molecule with previously reported antiviral activity, TMPyP4, interacts with MPXV G-quadruplexes with nanomolar affinity in the presence and absence of DHX36. Finally, cell biology experiments suggests that TMPyP4 treatment substantially reduced gene expression of MPXV proteins. In summary, our work provides insights into the G-quadruplexes from the MPXV genome that can be further exploited to develop therapeutics.

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Section: Biophysical Characterization Is Consistent With Mp1 and Mp2supporting

confidence: 79%

Mapping and characterization of G‐quadruplexes in monkeypox genomes

Pereira

Gemmill

Siddiqui

et al. 2023

Journal of Medical Virology

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“…23,46 Furthermore, an enantiomeric mirror-image form of G4 (L-G4) with left-handed backbone progression also exhibit binding to Rhau53 due to the presence of exposed tetrads, albeit with lower affinity. 48 In another study, preferential bindings to specific mirror-image forms of G4 were displayed by multiple enantiomeric compounds. 49 On the contrary, neither RHAU nor Phen-DC 3 can bind specifically to left-handed G4s formed by natural DNA, indicating that the loops in left-handed G4s involved in T-capping are tight and inflexible, preventing the docking of the ligands on the tetrads.…”

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confidence: 97%

Tetrad-binding ligands do not bind specifically to left-handed G-quadruplexes

Das

Phan

2022

Chem. Commun.

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“…There was 0.5 s/nm responding time, and all of the spectra recorded were averaged with 2 times of scanning. The data obtained were then normalized for the finding of the molar residue ellipticity and then smoothed over 5 nm . Spectra Manager Suite (Jasco Software) and Microsoft Excel were used to undergo all analyses with the collected data.…”

Section: Methodsmentioning

confidence: 99%

“…The data obtained were then normalized for the finding of the molar residue ellipticity and then smoothed over 5 nm. 55 (Jasco Software) and Microsoft Excel were used to undergo all analyses with the collected data.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

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Novel L-RNA Aptamer Controls APP Gene Expression in Cells by Targeting RNA G-Quadruplex Structure

Zhao

Wong

et al. 2022

ACS Appl. Mater. Interfaces

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Guanine quadruplex (G4) structure is a four-stranded nucleic acid secondary structure motif with unique chemical properties and important biological roles. Amyloid precursor protein (APP) is an Alzheimer’s disease (AD)-related gene, and recently, we reported the formation of RNA G4 (rG4) at the 3′UTR of APP mRNA and demonstrated its repressive role in translation. Herein, we apply rG4-SELEX to develop a novel L-RNA aptamer, L-Apt.8f, which binds to APP 3′UTR D-rG4 strongly with subnanomolar affinity. We structurally characterize the aptamer and find that it contains a thermostable and parallel G4 motif, and mutagenesis analysis identifies the key nucleotides that are involved in the target recognition. We also reveal that the L-Apt.8f–APP D-rG4 interaction is enantiomeric-, magnesium ion-, and potassium ion-dependent. Notably, L-Apt.8f preferentially recognizes APP rG4 over other structural motifs, and it can control the APP reporter gene and native transcript translation in cells. Our work introduces a novel strategy and reports a new L-aptamer candidate to target APP 3′UTR rG4 structure, which laid the foundation for further applying L-RNA as an important class of biomolecule for practical L-aptamer-based targeting and controlling of gene expression in cells.

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Effect of RNA sequence context and stereochemistry on G-quadruplex-RHAU53 interaction

Cited by 4 publications

References 15 publications

Mapping and characterization of G‐quadruplexes in monkeypox genomes

Mapping and characterization of G‐quadruplexes in monkeypox genomes

Tetrad-binding ligands do not bind specifically to left-handed G-quadruplexes

Novel L-RNA Aptamer Controls APP Gene Expression in Cells by Targeting RNA G-Quadruplex Structure

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