Effect of ATRX and G‐Quadruplex Formation by the VNTR Sequence on α‐Globin Gene Expression

Li, Yue; Syed, Junetha; Suzuki, Yuki; Asamitsu, Sefan; Shioda, Norifumi; Wada, Takahito; Sugiyama, Hiroshi

doi:10.1002/cbic.201500655

Cited by 25 publications

(24 citation statements)

References 61 publications

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“…G-quadruplex motifs broadly influence transcription and translation 41 . In addition, ATRX can either repress or activate gene expression through G-quadruplexes 9,51,52 . Although potential off-target effects remain to be investigated, our findings suggest a novel therapeutic strategy aimed at blocking Xlr3b expression through small molecule binding to G-quadruplex DNA in patients with ATR-X syndrome.…”

Section: Discussionmentioning

confidence: 99%

Targeting G-quadruplex DNA as cognitive function therapy for ATR-X syndrome

Shioda

Yabuki

Yamaguchi

et al. 2018

Nat Med

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Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX, which encodes a chromatin-remodeling protein. Genome-wide analyses in mouse and human cells indicate that ATRX tends to bind to G-rich sequences with a high potential to form G-quadruplexes. Here, we report that Atrx mutation induces aberrant upregulation of Xlr3b expression in the mouse brain, an outcome associated with neuronal pathogenesis displayed by ATR-X model mice. We show that ATRX normally binds to G-quadruplexes in CpG islands of the imprinted Xlr3b gene, regulating its expression by recruiting DNA methyltransferases. Xlr3b binds to dendritic mRNAs, and its overexpression inhibits dendritic transport of the mRNA encoding CaMKII-α, promoting synaptic dysfunction. Notably, treatment with 5-ALA, which is converted into G-quadruplex-binding metabolites, reduces RNA polymerase II recruitment and represses Xlr3b transcription in ATR-X model mice. 5-ALA treatment also rescues decreased synaptic plasticity and cognitive deficits seen in ATR-X model mice. Our findings suggest a potential therapeutic strategy to target G-quadruplexes and decrease cognitive impairment associated with ATR-X syndrome.

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Section: Discussionmentioning

confidence: 99%

Targeting G-quadruplex DNA as cognitive function therapy for ATR-X syndrome

Shioda

Yabuki

Yamaguchi

et al. 2018

Nat Med

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“…A G-quadruplex (G4) is an alternative form of DNA or RNA comprising several planar layers of four guanines (G-tetrads) held together via Hoogsteen hydrogen bonding (Figure 1) [1,2,3,4,5]. The G4 DNA has long been studied from various aspects and is now considered to be an important player in biological and biomedical events, including the control of promoter activity [6,7,8,9], genome instability [10,11,12,13], benchmarks for specified chromatin remodeling and replication [14,15], and epigenetic alterations [16,17]. The sequences, 5′-G ≥3 N 1–7 G ≥3 N 1–7 G ≥3 N 1–7 G ≥3 -3′, are advocated as consensus sequences that have the ability to form intramolecular G4s [18,19], although several exceptions have been reported at the present time [20,21,22,23,24].…”

Section: Introductionmentioning

confidence: 99%

Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy

et al. 2019

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A G-quadruplex (G4) is a well-known nucleic acid secondary structure comprising guanine-rich sequences, and has profound implications for various pharmacological and biological events, including cancers. Therefore, ligands interacting with G4s have attracted great attention as potential anticancer therapies or in molecular probe applications. To date, a large variety of DNA/RNA G4 ligands have been developed by a number of laboratories. As protein-targeting drugs face similar situations, G-quadruplex-interacting drugs displayed low selectivity to the targeted G-quadruplex structure. This low selectivity could cause unexpected effects that are usually reasons to halt the drug development process. In this review, we address the recent research on synthetic G4 DNA-interacting ligands that allow targeting of selected G4s as an approach toward the discovery of highly effective anticancer drugs.

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“…stranded overhang of telomeric DNA [7][8][9]. Most notably, it has been shown that quadruplex formation is directly involved in biologically relevant processes [10], for example, in the suppression of gene expression [11,12] or the induction of the cellular response to DNA damage [13,14]. Because of the increasing evidence of an essential biological function of G4-DNA, this DNA form is considered as an attractive target in drug development [1,2,15,16].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

Becher¹,

Berdnikova²,

Ihmels³

et al. 2020

Beilstein J. Org. Chem.

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A small series of five novel berberine derivatives was synthesized by the Cu-catalyzed click reaction of 9-propargyladenine with 9-O-(azidoalkyl)berberine derivatives. The association of the resulting berberine–adenine conjugates with representative quadruplex-forming oligonucleotides 22AG dA(G3TTA)3G3 and a2 d(ACAG4TGTG4)2 was examined with photometric and fluorimetric titrations, thermal DNA denaturation analysis, and CD spectroscopy. The results from the spectrometric titrations indicated the formation of 2:1 or 1:1 complexes (ligand:G4-DNA) with log K b values of 10–11 (2:1) and 5–6 (1:1), which are typical for berberine derivatives. Notably, a clear relationship between the binding affinity of the ligands with the length of the alkyl linker chain, n, was not observed. However, depending on the structure, the ligands exhibited different effects when bound to the G4-DNA, such as fluorescent light-up effects and formation of ICD bands, which are mostly pronounced with a linker length of n = 4 (with a2) and n = 5 (with 22AG), thus indicating that each ligand–G4-DNA complex has a specific structure with respect to relative alignment and conformational flexibility of the ligand in the binding site. It was shown exemplarily with one representative ligand from the series that such berberine–adenine conjugates exhibit a selective binding, specifically a selectivity to quadruplex DNA in competition with duplex DNA, and a preferential thermal stabilization of the G4-DNA forms 22AG and KRAS. Notably, the experimental data do not provide evidence for a significant effect of the adenine unit on the binding affinity of the ligands, for example, by additional association with the loops, presumably because the adenine residue is sterically shielded by the neighboring triazole unit.

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Effect of ATRX and G‐Quadruplex Formation by the VNTR Sequence on α‐Globin Gene Expression

Cited by 25 publications

References 61 publications

Targeting G-quadruplex DNA as cognitive function therapy for ATR-X syndrome

Targeting G-quadruplex DNA as cognitive function therapy for ATR-X syndrome

Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

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