DEAD-box helicase 17 (DDX17) protects cardiac function by promoting mitochondrial homeostasis in heart failure

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 24, 2024

Abstract DEAD-box helicase 17 (DDX17) is a typical member of the family with transcriptional cofactor activity. Although DDX17 abundantly expressed in myocardium, its role heart not fully understood. We generated cardiomyocyte-specific Ddx17- knockout mice ( Ddx17 -cKO), transgenic -Tg), and various models cardiomyocyte injury failure (HF). downregulated myocardium mouse injury. Cardiomyocyte-specific promotes autophagic flux blockage apoptosis, leading to progressive cardiac dysfunction, maladaptive remodeling progression failure. Restoration expression cardiomyocytes protects function under pathological conditions. Further studies showed that can bind repressor B-cell lymphoma 6 (BCL6) inhibit dynamin-related protein 1 (DRP1). When reduced, repression BCL6 attenuated, increased DRP1 mitochondrial fission, which turn leads impaired homeostasis also investigated correlation myocardial biopsy samples from patients These findings suggest by promoting through BCL6-DRP1 pathway

Language: Английский

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The Story of RNA Unfolded: The Molecular Function of DEAD- and DExH-Box ATPases and Their Complex Relationship with Membraneless Organelles

Annual Review of Biochemistry, Journal Year: 2024, Volume and Issue: 93(1), P. 79 - 108

Published: April 10, 2024

DEAD- and DExH-box ATPases (DDX/DHXs) are abundant highly conserved cellular enzymes ubiquitously involved in RNA processing. By remodeling RNA–RNA RNA–protein interactions, they often function as gatekeepers that control the progression of diverse maturation steps. Intriguingly, most DDX/DHXs localize to membraneless organelles (MLOs) such nucleoli, nuclear speckles, stress granules, or processing bodies. Recent findings suggest not only localization MLOs can promote interaction between their targets but also key regulators MLO formation turnover through condensation ATPase activity.In this review, we describe molecular ribosome biogenesis, messenger splicing, export, translation, storage decay well association with prominent MLOs. We discuss how enzymatic is linked DDX/DHX condensation, accumulation ribonucleoprotein particles dynamics. Future research will reveal these processes orchestrate life cycle space time.

Language: Английский

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Single-cell Rapid Capture Hybridization sequencing to reliably detect isoform usage and coding mutations in targeted genes

Genome Research, Journal Year: 2025, Volume and Issue: unknown, P. gr.279322.124 - gr.279322.124

Published: Jan. 10, 2025

Single-cell long-read sequencing has transformed our understanding of isoform usage and the mutation heterogeneity between cells. Despite unbiased in-depth analysis, low throughput often results in insufficient read coverage thereby limiting ability to perform calling for specific genes. Here, we developed a single-cell Rapid Capture Hybridization (scRaCH-seq) method that demonstrated high specificity efficiency capturing targeted transcripts using sequencing, allowing an analysis status transcript genes interest. The includes creating probe panel capture, barcoded primers pooling efficient via Oxford Nanopore Technologies platforms. scRaCH-seq is applicable stored indexed cDNA which allows be combined with existing short-read RNA-seq datasets. In investigation BTK SF3B1 samples from patients chronic lymphocytic leukaemia (CLL), detected isoforms mutations sensitivity. Integration scRNA-seq data revealed significant gene expression differences -mutated CLL cells, though it did not impact sensitivity anti-cancer drug venetoclax. scRaCH-seq's capability study multiple makes powerful tool genomics.

Language: Английский

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Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: Aug. 19, 2023

Abstract There is increasing evidence indicating the significant role of DDX5 (also called p68), acting as a master regulator and potential biomarker target, in tumorigenesis, proliferation, metastasis treatment resistance for cancer therapy. However, has also been reported to act an oncosuppressor. These seemingly contradictory observations can be reconciled by DDX5’s DNA repair. This because cell apoptosis malignant transformation represent two possible outcomes single process regulated DDX5, reflecting different intensity damage. Thus, targeting could potentially shift cells from growth-arrested state (necessary repair) killing. In addition increasingly recognized global genome stability surveillance damage repair, implicated multiple oncogenic signaling pathways. appears utilize distinct cascades via interactions with unique proteins types tissues/cells elicit opposing roles (e.g., smooth muscle versus cells). Such features make intriguing therapeutic target human cancers, limited low toxicity normal tissues. this review, we discuss multifaceted functions repair cancer, immune suppression, metabolic rewiring, virus infection promotion, negative impact on microbiome (microbiota). We provide new data showing that FL118, molecular glue degrader, selectively works against current treatment-resistant prostate organoids/cells. Altogether, studies demonstrate may oncotarget effectively conquering minimal

Language: Английский

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Programmable RNA writing with trans-splicing

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 1, 2024

RNA editing offers the opportunity to introduce either stable or transient modifications nucleic acid sequence without permanent off-target effects, but installation of arbitrary edits into transcriptome is currently infeasible. Here, we describe Programmable Editing & Cleavage for Insertion, Substitution, and Erasure (PRECISE), a versatile method writing length existing pre-mRNAs via 5' 3' trans-splicing. In trans-splicing, an exogenous template introduced compete with endogenous pre-mRNA, allowing replacement upstream downstream exon sequence. Using Cas7-11 cleavage bias towards outcomes, boost efficiency trans-splicing by 10-100 fold, achieving rates between 5-50% 85% on reporter transcripts, respectively, while maintaining high-fidelity. We demonstrate PRECISE across 11 distinct transcripts widely varying expression levels, showcasing more than 50 types edits, including all 12 possible transversions transitions, insertions ranging from 1 1,863 nucleotides, deletions. show high 4 MECP2, addressing most mutations that drive Rett Syndrome; SHANK3 gene involved in Autism; HTT, removing hallmark repeat expansions Huntington's disease. Whole sequencing reveals precision lack activity. Furthermore, combine payload engineering ribozymes protein-free, high-efficiency demonstrated HTT AAV delivery. activity enables non-dividing neurons patient-derived disease fibroblasts. markedly broadens scope genetic editing, straightforward deliver over tools like prime lacks off-targets, can enable any type edit large small, not otherwise base editors, widening spectrum addressable diseases.

Language: Английский

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One-Shot Single-Cell Proteome and Metabolome Analysis Strategy for the Same Single Cell

Analytical Chemistry, Journal Year: 2024, Volume and Issue: 96(14), P. 5499 - 5508

Published: March 28, 2024

Characterizing the profiles of proteome and metabolome at single-cell level is great significance in multiomic studies. Herein, we proposed a novel strategy called one-shot analysis (scPMA) to acquire information individual one injection LC-MS/MS analysis. Based on scPMA strategy, total workflow was developed achieve capture, nanoliter-scale sample pretreatment, LC separation enzyme-digested peptides metabolites, dual-zone MS/MS detection for profiling. Benefiting from realized dual-omic single tumor cells, including A549, HeLa, HepG2 cells with 816, 578, 293 protein groups 72, 91, 148 metabolites quantified average. A perspective experiment investigating doxorubicin-induced antitumor effects both aspects also performed.

Language: Английский

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CTCF and Its Multi-Partner Network for Chromatin Regulation

Cells, Journal Year: 2023, Volume and Issue: 12(10), P. 1357 - 1357

Published: May 10, 2023

Architectural proteins are essential epigenetic regulators that play a critical role in organizing chromatin and controlling gene expression. CTCF (CCCTC-binding factor) is key architectural protein responsible for maintaining the intricate 3D structure of chromatin. Because its multivalent properties plasticity to bind various sequences, similar Swiss knife genome organization. Despite importance this protein, mechanisms action not fully elucidated. It has been hypothesized versatility achieved through interaction with multiple partners, forming complex network regulates folding within nucleus. In review, we delve into CTCF’s interactions other molecules involved processes, particularly histone DNA demethylases, as well several long non-coding RNAs (lncRNAs) able recruit CTCF. Our review highlights partners shed light on regulation pave way future exploration enable finely-tuned master regulator

Language: Английский

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Diagnostic Power of MicroRNAs in Melanoma: Integrating Machine Learning for Enhanced Accuracy and Pathway Analysis

Journal of Cellular and Molecular Medicine, Journal Year: 2025, Volume and Issue: 29(2)

Published: Jan. 1, 2025

ABSTRACT This study identifies microRNAs (miRNAs) with significant discriminatory power in distinguishing melanoma from nevus, notably hsa‐miR‐26a and hsa‐miR‐211, which have exhibited diagnostic potential accuracy of 81% 78% respectively. To enhance accuracy, we integrated miRNAs into various machine‐learning (ML) models. Incorporating AUC scores above 0.70 significantly improved to 94%, a sensitivity 91%. These findings underscore the ML models leverage miRNA data for enhanced diagnosis. Additionally, using miRNet tool, constructed network miRNA–miRNA interactions, revealing 170 key genes pathophysiology. Protein–protein interaction analysis via Cytoscape identified hub including MYC, BRCA1, JUN, AURKB, CDKN2A, DDX5, MAPK14, DDX3X, DDX6, FOXM1 GSK3B. The identification their interactions enhances our understanding molecular mechanisms driving melanoma. Pathway enrichment analyses highlighted pathways associated differentially expressed miRNAs, PI3K/AKT, TGF‐beta signalling pathway cell cycle regulation. are implicated development progression, reinforcing significance findings. functional suggests critical role modulating essential melanoma, suggesting as therapeutic targets.

Language: Английский

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PAK4 promotes the cytoskeletal organization and meiotic maturation via phosphorylating DDX17 in oocyte

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 13, 2025

Language: Английский

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Biallelic PAX7 variants cause a novel Satellite Cell-opathy with progressive muscle involvement resembling facioscapulohumeral muscular dystrophy

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Abstract Inherited myopathies are genetic disorders characterised by declining motor function due to progressive muscle weakening and wasting. Recently, pathogenic variants in PAX7 , the master transcriptional regulator of stem cells, have been associated with variable severity, arguing for impaired satellite cell as main driver. Here, we report characterisation two missense a patient asymmetric, weakness affecting facial, upper lower body muscles, myopathic changes on pathology. Despite this disorder closely phenocopied clinical presentation Facioscapulohumeral muscular dystrophy (FSHD), epigenetic profiling was inconclusive FSHD, exome sequencing revealed heterozygous : c.335C>T, (p.Pro112Leu) c.1328G>A (p.Cys443Tyr). Modelling these human myoblasts resembled transcriptomic findings found biopsy from patient. Specifically, caused upregulation splicing factors, increase mitochondrial reactive oxygen species levels reduced proliferation, pathomechanism where diminished impairs homeostasis. Together, multimodal investigation suggests that likely causative an FSHD-like autosomal recessive myopathy expand spectrum neuromuscular originating form function.

Language: Английский

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