Small molecule-based regulation of gene expression in human astrocytes switching on and off the G-quadruplex control systems

Journal of Biological Chemistry, Год журнала: 2024, Номер 301(1), С. 108040 - 108040

Опубликована: Ноя. 29, 2024

Язык: Английский

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Why to target G‐quadruplexes using peptides: Next‐generation G4‐interacting ligands

Journal of Peptide Science, Год журнала: 2023, Номер 29(10)

Опубликована: Апрель 3, 2023

Guanine‐rich oligonucleotides existing in both DNA and RNA are able to fold into four‐stranded secondary structures via Hoogsteen type hydrogen‐bonding, where four guanines self‐assemble a square planar arrangement, which, when stacked upon each other, results the formation of higher‐order called G‐quadruplexes. Their distribution is not random; they more frequently present at telomeres, proto‐oncogenic promoters, introns, 5′‐ 3′‐untranslated regions, stem cell markers, ribosome binding sites so forth associated with various biological functions, all which play pivotal role incurable diseases like cancer cellular ageing. Several studies have suggested that G‐quadruplexes could regulate processes by themselves; instead, proteins take part this regulation can be important therapeutic targets. There certain limitations using whole G4‐protein for therapeutics purpose because its high manufacturing cost, laborious structure prediction, dynamic nature, unavailability oral administration due degradation gut inefficient penetration reach target site large size. Hence, biologically active peptides potential candidates intervention instead complex. In review, we aimed clarify roles G4s, how identify them throughout genome bioinformatics, interacting G4s G4‐interacting peptide molecules may next‐generation ligands targeting G4 motifs located regions.

Язык: Английский

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Expression of targets of the RNA-binding protein AUF-1 in human airway epithelium indicates its role in cellular senescence and inflammation

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Июль 7, 2023

Introduction The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described bronchiolar epithelium COPD patients versus controls vitro cytokine- cigarette smoke-challenged human airway epithelial cells, prompting the identification AUF-1-targeted transcripts function, investigation on mechanism its loss. Results RNA immunoprecipitation-sequencing (RIP-Seq) identified, cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched their 3’-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. association with selected synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets’ steady-state levels equally affected partial or near-total loss induced cytomix (TNFα/IL1β/IFNγ/10 nM each) siRNA, respectively, differential transcript decay rates. Cytomix-mediated decrease BEAS-2B primary small-airways (HSAEC) replicated treatment senescence- inducer compound etoposide associated readouts cell-cycle arrest, increase lysosomal damage senescence-associated secretory phenotype (SASP) factors, transfer extracellular vesicles, detected transmission electron microscopy immunoblotting. Extensive in-silico genome ontology analysis found, consistent functions, RIP-Seq-derived AUF-1-targets COPD-related pathways inflammation, gene also public SASP proteome atlas; target signature significantly represented multiple transcriptomic databases generated from HSAEC, lung tissue single-cell RNA-sequencing, displaying predominant downregulation expression. Discussion Loss intracellular may alter targets particularly relevant protection genomic integrity regulation, thus concurring inflammatory responses related oxidative stress accelerated aging. Exosomal-associated turn preserve bound sustain participating spreading senescence neighbouring cells.

Язык: Английский

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DHX36 maintains genomic integrity by unwinding G‐quadruplexes

Genes to Cells, Год журнала: 2023, Номер 28(10), С. 694 - 708

Опубликована: Авг. 26, 2023

The guanine-rich stretch of single-stranded DNA (ssDNA) forms a G-quadruplex (G4) in fraction genic and intergenic chromosomal regions. probability G4 formation increases during events causing ssDNA generation, such as transcription replication. In turn, abrogates these events, leading to damage. DHX36 unwinds G4-DNA vitro human cells. However, its spatial correlation with vivo role genome maintenance remain unclear. Here, we demonstrate connection between implications for genomic integrity. nuclear localization overlapped that G4-DNA, RNA polymerase II, splicing-related factor. Depletion resulted accumulated damage, slower cell growth, enhanced growth inhibition upon treatment G4-stabilizing compound; expression reversed defects. contrast, the reversal mutants could not bind was imperfect. Thus, may suppress damage by promoting clearance survival. Our findings deepen understanding resolution

Язык: Английский

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The Role of Tau Pathology in Alzheimer’s Disease and Down Syndrome

Опубликована: Янв. 25, 2024

. The Tau protein is associated with microtubule function in the neuron and crucial for normal axonal transport. In several different neurodegenerative disorders, misfolding leads to hyper-phosphorylation (p-Tau) intracellular p-Tau aggregates known as neurofibrillary tangles (NFTs). This particularly evident individuals Down syndrome (DS), who develop Alzheimer’s disease-like (AD) neuropathology early life almost complete penetrance, development of dementia symptoms their 40s or 50s. Our previous findings have shown that certain forms are present already childhood DS neuron-derived exosomes, suggesting an phosphorylation profile this population could influence AD pathology. Misfolded isoforms be seeding competent may responsible spreading pathology regions brain. review focused on accumulation brain potential consequences function.

Язык: Английский

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YLR419W is the homolog of the mammalian translation initiation factor

microPublication biology, Год журнала: 2024, Номер 2024

Опубликована: Янв. 1, 2024

27 years after the yeast genome sequencing, function of many ORFs remain unknown. Despite evolutionary distance between human and yeast, homology with conserved DEAH/DExH-box helicase domains allowed us to list DHX29, DHX36 DHX57 as three putative homologs Ylr419wp. Functional studies first linked Ylr419w protein translating ribosome cross-linking analysis cDNA (CRAC) experiments determined precise region Ylr419wp in contact ribosome. It corresponds loop h16 helix 18S rRNA designing translation initiation factor functional homolog

Язык: Английский

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RNA G-quadruplexes and calcium ions synergistically induce Tau phase transition in vitro

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(12), С. 107971 - 107971

Опубликована: Ноя. 5, 2024

Язык: Английский

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The emerging role of DEAD/H-box helicases in hepatitis B virus infection

Frontiers in Cellular and Infection Microbiology, Год журнала: 2022, Номер 12

Опубликована: Ноя. 25, 2022

DEAD/H-box helicases are an essential protein family with a conserved motif containing unique amino acid sequences (Asp-Glu-Ala-Asp/His). Current evidence indicates that regulate RNA metabolism and innate immune responses. In recent years, have been reported to participate in the development of variety diseases, including hepatitis B virus (HBV) infection, which is significant risk factor for hepatic fibrosis, cirrhosis, liver cancer. Furthermore, emerging suggests different play vital roles regulation viral replication, based on interaction HBV modulation signaling pathways mediated by helicases. Besides these, can alter expression activity facilitate its biosynthesis. More importantly, current investigation targeting appropriate compounds attractive treatment strategy infection. this review, we delineate advances molecular mechanisms relevant interplay helicase potential eliminate

Язык: Английский

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Disruption of a DNA G-quadruplex causes a gain-of-function <italic>SCL45A1</italic> variant relevant to developmental disorders

Acta Biochimica et Biophysica Sinica, Год журнала: 2024, Номер 56(5), С. 709 - 716

Опубликована: Апрель 24, 2024

SLC45A1 encodes a glucose transporter protein highly expressed in the brain. Mutations SLC45A1 may lead to neurological diseases and developmental disorders, but its exact role is poorly understood. DNA G-quadruplexes (DNA G4s) are stable structures formed by four guanine bases play gene regulation genomic stability. Changes G4s affect brain development function. The mechanism linking alterations G-quadruplex pathogenicity remains unknown. In this study, we identify functional key binding site on (NM_001080397.3: exon 2: c.449 G>A: p.R150K). This variant results upregulation of mRNA expression, which intellectual disorder with neuropsychiatric features. Mechanistically, mutation found disrupt SLC45A1, leading transcriptional enhancement gain-of-function mutation, further causes increased expression function SLC45A1 protein. identification effects provide new insights into genetic basis highlight importance regulating development.

Язык: Английский

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The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 4, 2024

Язык: Английский

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