Exploring the Role of G-Quadruplex DNA, and their Structural Polymorphism, in Targeting Small Molecules for the Design of Anticancer Therapeutics: Progress, Challenges, and Future Directions

Biochimie, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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CGG repeats in the human FMR1 gene regulate mRNA localization and cellular stress in developing neurons

Cell Reports, Год журнала: 2024, Номер 43(6), С. 114330 - 114330

Опубликована: Июнь 1, 2024

The human genome has many short tandem repeats, yet the normal functions of these repeats are unclear. 5′ untranslated region (UTR) fragile X messenger ribonucleoprotein 1 (FMR1) gene contains polymorphic CGG length which differing effects on FMR1 expression and health, including neurodevelopmental disorder syndrome. We deleted in (0CGG) stem cells examined differentiated neurons. 0CGG neurons have altered subcellular localization mRNA protein, differential cellular stress proteins compared with (31CGG). In addition, responses to glucocorticoid receptor (GR) activation, localization, GR chaperone HSP90α expression, protein levels. Therefore, important for homeostatic signals.

Язык: Английский

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G-Tetrad-Selective Ligand Binding Kinetics in G-Quadruplex DNA Probed with Fluorescence Correlation Spectroscopy

The Journal of Physical Chemistry B, Год журнала: 2022, Номер 126(32), С. 6007 - 6015

Опубликована: Авг. 8, 2022

Probing the kinetics of ligand binding to biomolecules is paramount interest in biology and pharmacology. Measurements such kinetic processes provide information on rate-determining steps that control affinity ligands biomolecules, thereby predicting mechanism molecular interaction. In this context, G-quadruplex DNA (GqDNA) structures has attracted tremendous attention primarily because their use possible anticancer therapy. Although a large number G-quadruplex-specific have been proposed, probing G-tetrad-selective (multiple) within structure remains challenging. Most earlier studies focused thermodynamics binding; however, association dissociation with GqDNA, particularly multiple GqDNA structure, not explored. Here, we propose simple fluorescence correlation spectroscopy-based method measures rates by correlating fluctuations site-specific (5′ or 3′ end-labeled) fluorophore (Cy3) due quenching Cy3 fluorescence, induced G-tetrads. We show well-known ligands, BRACO19, TMPyP4, Hoechst 33258, 33342, rates, which suggest site-dependent variation free energy barriers for binding/unbinding GqDNA. also measured depend only G-tetrad site vs end) but structures.

Язык: Английский

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Leveraging DNA‐Encoded Cell‐Mimics for Environment‐Adaptive Transmembrane Channel Release‐Induced Cell Death

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(30)

Опубликована: Май 13, 2024

Abstract The advancement of cell‐mimic materials, which can forge sophisticated physicochemical dialogues with living cells, has unlocked a realm intriguing prospects within the fields synthetic biology and biomedical engineering. Inspired by evolutionarily acquired ability T lymphocytes to release perforin generate transmembrane channels on targeted cells for killing, herein we present pioneering DNA‐encoded artificial cell mimic model (ARTC) that accurately mimics T‐cell‐like behavior. ARTC responds acidic conditions similar those found in tumor microenvironment then selectively releases G‐rich DNA strand (LG4) embedded C12 lipid cholesterol molecules. Once released, LG4 effectively integrates into membranes neighboring live behaving as an channel transports K + ions disrupts cellular homeostasis, ultimately inducing apoptosis. We hope emergence will usher new perspectives revolutionizing future disease treatment catalyzing development advanced technologies.

Язык: Английский

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Discovery of A G‐Quadruplex Unwinder That Unleashes the Translation of G‐Quadruplex‐Containing mRNA without Inducing DNA Damage

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(38)

Опубликована: Июль 2, 2024

To explore the mechanisms and therapeutic strategies for G-quadruplex (G4) mediated diseases, it is crucial to manipulate intervene in intracellular G4 structures using small molecular tools. While hundreds of stabilizers have been developed, there a significant gap availability unwinding agents. Here, we propose strategy disrupt G-quadruplexes by forming G-C hydrogen bonds with chemically modified cytidine trimers. We validated good unwinder, 2'-F trimer (2'-F C3). C3 does not inhibit cell growth nor cause severe DNA damage at concentration below 10 μM. Moreover, affect gene transcription RNA splicing, while significantly enhances translation G4-containing mRNA upregulates processing cycle pathways. The discovery this unwinder provides functional tool chemical modulation G4s living cells.

Язык: Английский

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Characterization of G-Quadruplexes in Enterovirus A71 Genome and Their Interaction with G-Quadruplex Ligands

Microbiology Spectrum, Год журнала: 2022, Номер 10(3)

Опубликована: Апрель 21, 2022

Human enteroviruses cause many diseases; however, there is no specific therapeutic drug. G-quadruplex an atypical secondary structure formed in the guanine rich region of DNA or RNA, which can exist viral genome. The different positions play important role regulation virus replication and infection. Whether G-quadruplexes are present human unknown. In current study, we analyzed potential quadruplex forming sequences enteroviruses, especially EV-A71 virus, causes hand, foot, mouth disease. results showed that were a certain number quadruplex-forming enteroviruses. Through variety experimental methods, evaluated formation encoded binding ability ligands, including BRACO-19, pyridostatin TMPyP4 to G-quadruplexes. ligands PDS could inhibit transcription constructs containing sequences. Moreover, found BRACO-19 was able EV-A71, suggesting targeting genome by be novel antiviral way against EV-A71. Our finding not only uncovered but also would provide new strategy for therapy. IMPORTANCE stable nucleic acid folding acid. regulatory function makes it attractive target effect. diseases, common cold, nervous system cardiovascular damage, diabetes. Enterovirus A71 (EV-A71) one pathogens causing disease; whether genomes clear. We predicted characterized identified stabilize with high affinities. demonstrated ligand inhibited replication. studies framework genome, will develop agents

Язык: Английский

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Role of NS2 specific RNA binding and phosphorylation in liquid–liquid phase separation and virus assembly

Nucleic Acids Research, Год журнала: 2022, Номер 50(19), С. 11273 - 11284

Опубликована: Окт. 19, 2022

Abstract Liquid–liquid phase separation (LLPS) has assumed a prominent role in biological cell systems, where it underpins the formation of subcellular compartments necessary for function. We investigated underlying mechanism LLPS virus infected cells, inclusion bodies are formed by an RNA-binding phosphoprotein (NS2) Bluetongue to serve as sites subviral particle assembly and maturation. show that NS2 undergoes is dependent on protein phosphorylation occurrence accompanied change secondary structure. Site-directed mutagenesis identified two critical arginine residues responsible specific RNA binding thus NS2–RNA complex driven LLPS. Reverse genetics same essential VIB cells viability. Our findings suggest arginine–RNA interaction context phosphorylated state drives this, possibly other, infections.

Язык: Английский

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IGF2BP1-Mediated Regulation of CCN1 Expression by Specific Binding to G-Quadruplex Structure in Its 3′UTR

Biochemistry, Год журнала: 2024, Номер 63(17), С. 2166 - 2182

Опубликована: Авг. 12, 2024

The intricate regulation of gene expression is fundamental to the biological complexity higher organisms, and primarily governed by transcriptional post-transcriptional mechanisms. 3′-untranslated region (3′UTR) mRNA rich in cis-regulatory elements like G-quadruplexes (G4s), plays a crucial role regulation. G4s have emerged as significant regulators, impacting stability, translation, localization. In this study, we investigate robust parallel G4 structure situated within 3′UTR CCN1 This proximal stop codon human CCN1, evolutionarily conserved. We elucidated its interaction with insulin-like growth factor 2 binding protein 1 (IGF2BP1), noncanonical RNA N6-methyladenosine (m6A) modification reader, revealing novel interplay between modifications G-quadruplex structures. Knockdown experiments mutagenesis studies demonstrate that IGF2BP1 binds specifically structure, modulating stability. Additionally, unveil IGF2BP1's recognition motifs recognition, highlighting enthalpically driven interaction. Our findings offer fresh perspectives on complex mechanisms mediated secondary

Язык: Английский

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Identification of sugar-containing natural products that interact with i-motif DNA

Bioorganic & Medicinal Chemistry Letters, Год журнала: 2022, Номер 73, С. 128886 - 128886

Опубликована: Июль 11, 2022

There are thousands of compounds shown to interact with G-quadruplex DNA, yet very few which target i-motif (iM) DNA. Previous work showed that tobramycin can iM- indicating the potential for sugar-molecules these structures. Computational approaches indicated sugar-containing natural products baicalin and geniposidic acid had iM-DNA. We assessed DNA interacting properties using FRET-based melting a fluorescence-based displacement assay iM-DNA structures from human telomere insulin linked polymorphic region (ILPR), as well complementary double stranded Both show promise iM-interacting use in experiments into structure function forming sequences present starting points further synthetic development probes

Язык: Английский

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Hydrophobic Interaction-Induced Topology-Independent Destabilization of G-Quadruplex

Biochemistry, Год журнала: 2023, Номер 62(23), С. 3430 - 3439

Опубликована: Ноя. 16, 2023

Since the inception of G-quadruplex (G4), enormous attention has been devoted to designing small molecules which can stabilize G-quadruplex. In contrast, knowledge about and mechanisms involved in destabilization G4 is sparse, although it well recognized that important neurobiology age-related genetic issues. this study, shown amphiphilic having a long hydrocarbon chain destabilize G4, regardless its topology, using various biophysical molecular dynamics simulation methods. It observed hydrophobic interaction induced by main contributor triggering hydrogen bonding polar part also cooperates process. The experiment studies suggest containing gets aggregated, their as group intrude quartet region from 5′ side interact with guanine bases nearby loops through electrostatic interactions, trigger G4.

Язык: Английский

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