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Keywords = splicing factors/RNA-binding proteins

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15 pages, 1700 KiB  
Article
PROM1 and EFTUD2 Expression in High-Grade Clear Cell Renal Cell Carcinoma as a Molecular Marker for Survival Rate
by Michał Kasperczak, Iga Kołodziejczak-Guglas, Filip Kasperczak, Maciej Wiznerowicz and Andrzej Antczak
Int. J. Mol. Sci. 2025, 26(13), 6296; https://doi.org/10.3390/ijms26136296 - 30 Jun 2025
Viewed by 458
Abstract
Clear cell renal cell carcinoma (ccRCC) is a significant global cancer, particularly impacting individuals in Western countries. Despite that, the molecular mechanisms driving renal cell carcinoma progression remain poorly understood, highlighting the need to investigate these mechanisms and identify novel therapeutic targets. Literature [...] Read more.
Clear cell renal cell carcinoma (ccRCC) is a significant global cancer, particularly impacting individuals in Western countries. Despite that, the molecular mechanisms driving renal cell carcinoma progression remain poorly understood, highlighting the need to investigate these mechanisms and identify novel therapeutic targets. Literature evidence suggests that elongation factor Tu GTP binding domain containing 2 (EFTUD2) and prominin (PROM1) gene expression have significant diagnostic potential in early tumor detection, potentially reflecting the trends in progression, and may become a novel therapeutic target. Therefore, this study aimed to evaluate EFTUD2 and PROM1 protein expression on clinical characteristics of ccRCC patients, especially overall and progression-free survival. To achieve that goal, we have combined publicly available liquid chromatography–mass spectrometry (LC-MS/MS) protein expression data with a comprehensive literature review to identify key protein markers for further study and immunohistochemical (IHC) analysis. Our findings highlight the importance of considering protein expression heterogeneity within tumors. The significant variation in EFTUD2 expression, its association with PFS, and its intricate connections with the mRNA splicing machinery underscore the need for a more nuanced understanding of its role in ccRCC. Similarly, the downregulation of PROM1 and its potential effects on cell surface interactions warrant further exploration. Future studies should focus on elucidating the mechanisms underlying these observations, exploring their potential as therapeutic targets, and investigating the specific pathways affected by their dysregulation. Full article
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44 pages, 4214 KiB  
Review
LncRNAOmics: A Comprehensive Review of Long Non-Coding RNAs in Plants
by Chinmay Saha, Saibal Saha and Nitai P. Bhattacharyya
Genes 2025, 16(7), 765; https://doi.org/10.3390/genes16070765 - 29 Jun 2025
Viewed by 1623
Abstract
The large portion of the eukaryotic genomes was considered non-functional and called the “dark matter” of the genome, now appearing as regulatory hubs coding for RNAs without the potential for making proteins, known as non-coding RNA. Long non-coding RNA (lncRNA) is defined as [...] Read more.
The large portion of the eukaryotic genomes was considered non-functional and called the “dark matter” of the genome, now appearing as regulatory hubs coding for RNAs without the potential for making proteins, known as non-coding RNA. Long non-coding RNA (lncRNA) is defined as functional RNA molecules having lengths larger than 200 nucleotides without the potential for coding for proteins. Thousands of lncRNAs are identified in different plants and animals. LncRNAs are characterized by a low abundance, fewer exons than mRNA, tissue-specific expression, and low sequence conservation compared to protein-coding genes (PCGs). LncRNAs, like PCGs, are regulated by promoters and enhancers with characteristic chromatin signatures, DNA methylation, multiple exons, introns, and alternate splicing. LncRNAs interact with DNA, mRNA, microRNA, and proteins, including chromatin/histone modifiers, transcription factors/repressors, epigenetic regulators, spliceosomal, and RNA-binding proteins. Recent observations indicate that lncRNAs code for small peptides, also called micropeptides (<100 amino acids), and are involved in the development and growth of plants, suggesting the bi-functional activities of lncRNAs. LncRNAs have emerged as the major regulators of diverse functions, principally by altering the transcription of target genes. LncRNAs are involved in plant growth, development, immune responses, and various physiological processes. Abiotic, biotic, nutrient, and other environmental stresses alter the expressions of numerous lncRNAs. Understanding the mechanisms of actions of lncRNAs opens up the possibility of improving agronomic traits by manipulating lncRNAs. However, further studies are required in order to find the interactions among the deregulated lncRNAs and validate the findings from high-throughput studies to harness their potential in crop improvement. Full article
(This article belongs to the Section RNA)
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17 pages, 2959 KiB  
Article
[Pd(dach)Cl2] Complex Targets Proteins Involved in Ribosomal Biogenesis, and RNA Splicing in HeLa Cells
by Vanja Ralić, Katarina Davalieva, Branislava Gemović, Milan Senćanski, Maja D. Nešić, Jelena Žakula, Milutin Stepić and Marijana Petković
Inorganics 2025, 13(7), 215; https://doi.org/10.3390/inorganics13070215 - 26 Jun 2025
Viewed by 446
Abstract
This study aims to investigate the effect of the Pd(II) complex on HeLa cells using computational biology and proteomic analysis. [Pd(dach)Cl2]-treated HeLa cells were subjected to comparative proteomics analysis using label-free data-independent liquid chromatography-tandem mass spectrometry (LC-MS/MS). In parallel, [...] Read more.
This study aims to investigate the effect of the Pd(II) complex on HeLa cells using computational biology and proteomic analysis. [Pd(dach)Cl2]-treated HeLa cells were subjected to comparative proteomics analysis using label-free data-independent liquid chromatography-tandem mass spectrometry (LC-MS/MS). In parallel, the informational spectrum method (ISM) was used to predict potential protein interactors of the [Pd(dach)Cl2] complex in HeLa cells. Proteomics analysis revealed 121 differentially abundant proteins (DAPs). Enrichment analysis of Gene Ontology (GO) annotations revealed ATP hydrolysis and RNA/protein binding as the top molecular functions and RNA splicing and protein–RNA complex organization as the top biological processes. Enrichment analysis of altered canonical pathways pointed out spliceosome and ribosome pathways. The top hub proteins with potential regulatory importance encompassed ribosomal proteins, translational and transcriptional factors, and components of the ribosome assembly machinery. ISM and cross-spectral analysis identified the nucleoplasm and sensor of the single-stranded DNA (SOSS DNA) complex. Proteome analysis showed that [Pd(dach)Cl2] targets proteins involved in ribosomal biogenesis and RNA splicing, whereas theoretical prediction implies also potential effect on p53 signaling pathway, and thus, alterations of the expression of regulatory proteins involved in cell survival and proliferation. These findings underscore the potential of Pd(II) complexes as anti-cancer agents, warranting further exploration and detailed functional validation. Full article
(This article belongs to the Special Issue Metal Complexes Diversity: Synthesis, Conformations, and Bioactivity)
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16 pages, 1060 KiB  
Review
Glucocorticoid Insensitivity: Is It a Question of Time and Place?
by Christopher Lambers and Michael Roth
Biomedicines 2025, 13(6), 1418; https://doi.org/10.3390/biomedicines13061418 - 10 Jun 2025
Viewed by 569
Abstract
Background: Glucocorticoid insensitivity is a problem for the therapy of chronic inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Both are non-communicable chronic inflammatory lung diseases with worldwide increasing incidences. Only symptoms can be controlled by inhaled or systemic [...] Read more.
Background: Glucocorticoid insensitivity is a problem for the therapy of chronic inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Both are non-communicable chronic inflammatory lung diseases with worldwide increasing incidences. Only symptoms can be controlled by inhaled or systemic glucocorticoids, often combined with β2 agonists and/or muscarinic receptor antagonists. The therapeutic effect of glucocorticoids varies between individuals, and a significant number of patients do not respond well. It is believed that only protein-free circulating unbound glucocorticoids can enter cells by diffusion and achieve their therapeutic effect by binding to the intracellular glucocorticoid receptor (GR), encoded by the NR3C1 gene, for which over 3000 single-nucleotide polymorphisms have been described. In addition, various GR protein isoforms result from 11 transcription start sites, and differential mRNA splicing leads to further GR protein variants; each can be modified post-translational and alter steroid response. To add more variety, some GR isoforms are expressed cell-type specific or in a sub-cellular location. The GR only functions when it forms a complex with other intracellular proteins that regulate ligand binding, cytosol-to-nuclear transport, and nuclear and cytosolic action. Importantly, the timing of the GR activity can be cell type, time, and condition specific. These factors are rarely considered when assessing disease-specific loss or reduced GR response. Conclusions: Future studies should analyze the timing of the availability, activity, and interaction of all components of the glucocorticoid signaling cascade(s) and compare these factors between non-diseased and diseased probands, applying the combination of all omics methods (250). Full article
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27 pages, 770 KiB  
Review
Alternative Splicing in Tumorigenesis and Cancer Therapy
by Huiping Chen, Jingqun Tang and Juanjuan Xiang
Biomolecules 2025, 15(6), 789; https://doi.org/10.3390/biom15060789 - 29 May 2025
Cited by 1 | Viewed by 1233
Abstract
Alternative splicing (AS) is a pivotal post-transcriptional mechanism that expands the functional diversity of the proteome by enabling a single gene to generate multiple mRNA and protein isoforms. This process, which involves the differential inclusion or exclusion of exons and introns, is tightly [...] Read more.
Alternative splicing (AS) is a pivotal post-transcriptional mechanism that expands the functional diversity of the proteome by enabling a single gene to generate multiple mRNA and protein isoforms. This process, which involves the differential inclusion or exclusion of exons and introns, is tightly regulated by splicing factors (SFs), such as serine/arginine-rich proteins (SRs), heterogeneous nuclear ribonucleoproteins (hnRNPs), and RNA-binding motif (RBM) proteins. These factors recognize specific sequences, including 5′ and 3′ splice sites and branch points, to ensure precise splicing. While AS is essential for normal cellular function, its dysregulation is increasingly implicated in cancer pathogenesis. Aberrant splicing can lead to the production of oncogenic isoforms that promote tumorigenesis, metastasis, and resistance to therapy. Furthermore, such abnormalities can cause the loss of tumor-suppressing activity, thereby contributing to cancer development. Importantly, abnormal AS events can generate neoantigens, which are presented on tumor cell surfaces via major histocompatibility complex (MHC) molecules, suggesting novel targets for cancer immunotherapy. Additionally, splice-switching oligonucleotides (SSOs) have shown promise as therapeutic agents because they modulate splicing patterns to restore normal gene function or induce tumor-suppressive isoforms. This review explores the mechanisms of AS dysregulation in cancer, its role in tumor progression, and its potential as a therapeutic target. We also discuss innovative technologies, such as high-throughput sequencing and computational approaches, that are revolutionizing the study of AS in cancer. Finally, we address the challenges and future prospects of targeting AS for personalized cancer therapies, emphasizing its potential in precision medicine. Full article
(This article belongs to the Section Molecular Genetics)
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25 pages, 1043 KiB  
Review
hnRNPH1: A Multifaceted Regulator in RNA Processing and Disease Pathogenesis
by Lijing Zhu, Wei Yi, Like Zhang, Chenyue Qiu, Ning Sun, Jingwen He, Ping Feng, Qiong Wu, Guangyi Wang and Guosheng Wu
Int. J. Mol. Sci. 2025, 26(11), 5159; https://doi.org/10.3390/ijms26115159 - 28 May 2025
Viewed by 957
Abstract
Heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) is a multifunctional RNA-binding protein (RBP) that plays a central role in post-transcriptional regulation. Through its quasi-RNA recognition motifs and low-complexity domains, hnRNPH1 specifically binds guanine-rich RNA sequences, including G-quadruplex structures, to precisely modulate multiple aspects of RNA [...] Read more.
Heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) is a multifunctional RNA-binding protein (RBP) that plays a central role in post-transcriptional regulation. Through its quasi-RNA recognition motifs and low-complexity domains, hnRNPH1 specifically binds guanine-rich RNA sequences, including G-quadruplex structures, to precisely modulate multiple aspects of RNA metabolism, such as alternative splicing, mRNA stability, translation, and subcellular localization. Accumulating evidence has implicated hnRNPH1 dysfunction in the pathogenesis of several human diseases. In cancer, hnRNPH1 often acts as a pro-tumorigenic factor, albeit in a context-dependent manner, influencing the alternative splicing of crucial oncogenes, mRNA stability, and tumor cell sensitivity to therapeutic agents. In the nervous system, hnRNPH1 is involved in neurodevelopment, neurodegenerative diseases, and drug addiction and plays an essential role in maintaining neuronal function and homeostasis. Furthermore, it exerts regulatory functions in reproductive system development and fertility and in non-neoplastic pathologies, including cardiovascular diseases, autoimmune disorders, and viral hepatitis. Given its pathophysiological significance, hnRNPH1 has emerged as a promising biomarker and therapeutic target. This review provides an overview of the structural basis and core molecular function of hnRNPH1. Its mechanisms of action and pathological significance in various diseases have also been detailed. Additionally, this review summarizes the current therapeutic strategies targeting hnRNPH1, discusses the associated challenges, outlines optimization approaches, and considers future research directions. Overall, this review aims to deepen our understanding of hnRNPH1 biology and inspire the development of novel diagnostic and therapeutic interventions. Full article
(This article belongs to the Section Molecular Biology)
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22 pages, 12709 KiB  
Article
IGF2BP3 Modulates mRNA Splicing and Stability to Promote Trophoblast Progression via Interaction with PDE3A and Suppression by miR-196a-5p in Preeclampsia
by Chunyan Li, Pingpo Ming, Cuifang Fan, Jiao Chen and Jing Yang
Biomedicines 2025, 13(6), 1268; https://doi.org/10.3390/biomedicines13061268 - 22 May 2025
Viewed by 612
Abstract
Background: Preeclampsia (PE) is a pregnancy-specific disorder and a leading cause of maternal and fetal morbidity and mortality. Impaired trophoblast invasion is a hallmark of PE, and alternative splicing (AS) is crucial for trophoblast differentiation and placental development. However, the exact mechanisms of [...] Read more.
Background: Preeclampsia (PE) is a pregnancy-specific disorder and a leading cause of maternal and fetal morbidity and mortality. Impaired trophoblast invasion is a hallmark of PE, and alternative splicing (AS) is crucial for trophoblast differentiation and placental development. However, the exact mechanisms of AS in PE remain poorly understood. Methods: To elucidate AS-mediated regulatory pathways in PE, a total of 38 fresh-frozen placental samples, including 13 pre-eclampsia samples and 25 normal control samples, were collected from Renmin Hospital of Wuhan University between 1 February and 30 July 2022. We performed transcriptome sequencing of seven PE and seven normal placentas to identify differentially spliced events. After quality control and adapter trimming, raw sequencing reads were aligned to the human reference genome using STAR. Differential exon usage was analyzed using DEXSeq (version 1.36.0), and exons with an adjusted p-value < 0.05 and a fold change greater than 2 or less than 0.5 were considered significantly differentially spliced. Functional assays, including CCK8, colony formation, and cell cycle analyses, were conducted to assess trophoblast proliferation, whereas wound healing and Transwell assays were used to evaluate trophoblast migration and invasion using the HTR-8/SVneo cell line. RNA immunoprecipitation sequencing (RIP-seq) and RNA stability assays were employed to investigate mRNA interactions and stability. Results: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) emerged as a key RNA-binding protein associated with alternative splicing regulation, intersecting both AS-related candidate genes and known splicing factors, although it is not a classical splicing factor itself. IGF2BP3 overexpression markedly enhanced HTR-8/SVneo trophoblast proliferation, migration, and invasion while suppressing ROS activation. RNA-seq, RIP-seq, and RNA stability assays revealed that IGF2BP3 directly interacts with and enhances the stability of PDE3A mRNA. Functional rescue experiments confirmed that PDE3A knockdown partially abrogated IGF2BP3-mediated trophoblast progression. Furthermore, miR-196a-5p was identified as a negative regulator of IGF2BP3 via miRNA inhibitor/mimic transfection, qRT-PCR, and functional assays, confirming that miR-196a-5p overexpression downregulates IGF2BP3, thereby impairing trophoblast migration and proliferation. Notably, restoring IGF2BP3 expression reversed these inhibitory effects. Conclusions: Our findings reveal a previously unrecognized regulatory axis in PE in which miR-196a-5p suppresses IGF2BP3 expression, leading to PDE3A mRNA destabilization and impaired trophoblast function. This study offers mechanistic insights into PE pathogenesis and identifies IGF2BP3 as a potential therapeutic target. Full article
(This article belongs to the Section Cell Biology and Pathology)
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33 pages, 688 KiB  
Review
The Regulatory Roles of RNA-Binding Proteins in Plant Salt Stress Response
by Tangying Wang, Kaiyuan Meng, Zilin Zhu, Linxuan Pan, Thomas W. Okita, Laining Zhang and Li Tian
Plants 2025, 14(9), 1402; https://doi.org/10.3390/plants14091402 - 7 May 2025
Cited by 1 | Viewed by 1767
Abstract
Salt stress is one of the most prominent abiotic stresses. Behind the intricate adaptive responses of plants to salt stress, the regulation of gene expression assumes a pivotal role. Complementing transcriptional mechanisms, post-transcriptional regulation performed by RNA-binding proteins provides an additional layer of [...] Read more.
Salt stress is one of the most prominent abiotic stresses. Behind the intricate adaptive responses of plants to salt stress, the regulation of gene expression assumes a pivotal role. Complementing transcriptional mechanisms, post-transcriptional regulation performed by RNA-binding proteins provides an additional layer of control through sophisticated molecular machinery. RBPs interact with both RNA molecules and protein partners to coordinate RNA metabolism and, thus, fine-tune the expression of salt-responsive genes, enabling plants to rapidly adapt to ionic challenges. This review systematically evaluates the functional roles of RBPs localized in distinct subcellular compartments, including nuclear, cytoplasmic, chloroplastic, and mitochondrial systems, in mediating post-transcriptional regulatory networks under salinity challenges. Specific classes of RBPs are discussed in detail, including glycine-rich RNA-binding proteins (GR-RBPs), serine/arginine-rich splicing factors (SR proteins), zinc finger domain-containing proteins, DEAD-box RNA helicases (DBRHs), KH domain-containing proteins, Pumilio domain-containing proteins (PUMs), pentatricopeptide repeat proteins (PPRs), and RBPs involved in cytoplasmic RNA granule formation. By integrating their subcellular localization and current mechanistic insights, this review concludes by summarizing the current knowledge and highlighting potential future research directions, aiming to inspire further investigations into the complex network of RBPs in modulating plant responses to salt stress and facilitating the development of strategies to enhance plant salt tolerance. Full article
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13 pages, 2008 KiB  
Brief Report
ACADVL Deep Sequencing in a Case Study: Beyond the Common c.848T>C Pathogenic Variant
by Francesco Baldo, Luisa Zupin, Andrea Magnolato, Valeria Capaci and Maria Teresa Bonati
Genes 2025, 16(5), 538; https://doi.org/10.3390/genes16050538 - 30 Apr 2025
Viewed by 662
Abstract
Background: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is caused by biallelic pathogenic variants in ACADVL (acyl-CoA dehydrogenase very-long-chain), leading to impaired fatty acid oxidation and the accumulation of long-chain acylcarnitine. We report a single case of a two-year-old girl, whose neonatal metabolic screening revealed [...] Read more.
Background: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is caused by biallelic pathogenic variants in ACADVL (acyl-CoA dehydrogenase very-long-chain), leading to impaired fatty acid oxidation and the accumulation of long-chain acylcarnitine. We report a single case of a two-year-old girl, whose neonatal metabolic screening revealed an acylcarnitine profile suggestive of VLCADD, with residual enzymatic activity of 19.8%. Methods: We performed ACADVL whole-gene sequencing. We then carried out an in silico analysis of the potential effects of the variants with dedicated tools, assessing splicing, RNA structure, RNA binding factors, and protein structure. We also conducted gene expression analysis. Results: Genetic testing identified her as compound heterozygous for the pathogenic ACADVL variant (NM_000018.3):c.848T>C, inherited from her mother, and for the two paternal variants, c.-64T>C in the basal promoter and c.957G>A, a synonymous substitution in exon 10. Gene expression analysis revealed reduced ACADVL mRNA levels in the proband’s blood cells but without abnormal isoform production. A decreased expression of the paternal allele carrying the 957A was also observed. Despite this significant reduction in mRNA levels, the underlying mechanism remains unclear. Conclusions: Although currently healthy, due to the VLCAD residual activity within the range associated with the mild form of the disease, the child might be at potential risk for metabolic decompensation or late-onset VLCADD. Our results indicated an allelic imbalance in mRNA expression and c.957G>A is identified as a hypomorphic allele. This suggests that deep ACADVL sequencing is a valuable tool for correlating genetic variants with enzymatic activity levels. Full article
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18 pages, 4051 KiB  
Article
Effects of Brimonidine, Latanoprost, and Omidenepag on Tunicamycin-Induced Endoplasmic Reticulum Stress and Fibrosis in Human Trabecular Meshwork Cells
by Mengxuan Liu, Megumi Honjo, Reiko Yamagishi and Makoto Aihara
Biomolecules 2025, 15(3), 389; https://doi.org/10.3390/biom15030389 - 8 Mar 2025
Viewed by 768
Abstract
This study evaluated the effects of α2-adrenergic agonist, prostaglandin F2α analog, and EP2 receptor agonist on tunicamycin-induced endoplasmic reticulum (ER) stress and fibrosis in human trabecular meshwork (TM) cells. Human TM cells were treated with tunicamycin for 24 h, followed by cotreatment with [...] Read more.
This study evaluated the effects of α2-adrenergic agonist, prostaglandin F2α analog, and EP2 receptor agonist on tunicamycin-induced endoplasmic reticulum (ER) stress and fibrosis in human trabecular meshwork (TM) cells. Human TM cells were treated with tunicamycin for 24 h, followed by cotreatment with brimonidine (BRI), latanoprost (LAT), or omidenepag (OMD). Immunocytochemistry was used to assess expressions of collagen type I alpha 1 chain (COL1A1), fibronectin, F-actin, and alpha-smooth muscle actin (α-SMA). Western blotting was performed to evaluate levels of C/EBP homologous protein (CHOP), 78-kDa glucose-regulated protein (GRP78), and splicing X-box binding protein-1 (sXBP-1). Real-time qPCR was used to examine the mRNA expressions of COL1A1, connective tissue growth factor (CTGF), fibronectin, α-SMA, CHOP, GRP78, and sXBP-1. Expressions of COL1A1, CTGF, F-actin, fibronectin, α-SMA, CHOP, GRP78, and sXBP-1 significantly increased after tunicamycin treatment. BRI cotreatment significantly downregulated the mRNA and protein expressions of GRP78, and LAT or OMD cotreatment significantly reduced the CHOP and sXBP-1 expressions compared to the tunicamycin-treated group. BRI, LAT, or OMD cotreatment significantly attenuated cellular cytoskeletal changes and the increase of fibrosis markers such as COL1A1, CTGF, fibronectin, and α-SMA. In addition, COL1A1 mRNA expression was significantly lowered with LAT or OMD cotreatment compared to the BRI-cotreated group. Cotreatment with α2-adrenergic agonist, prostaglandin F2α analog, or EP2 receptor agonist alleviates tunicamycin-induced ER stress in human TM cells. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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21 pages, 4753 KiB  
Article
Fabry Disease and Inflammation: Potential Role of p65 iso5, an Isoform of the NF-κB Complex
by Giuseppa Biddeci, Gaetano Spinelli, Paolo Colomba, Giovanni Duro, Monia Anania, Daniele Francofonte and Francesco Di Blasi
Cells 2025, 14(3), 230; https://doi.org/10.3390/cells14030230 - 6 Feb 2025
Cited by 1 | Viewed by 1438
Abstract
Fabry disease (FD) is an X-linked lysosomal storage disease, caused by mutations in the GLA gene on the X chromosome, resulting in a deficiency of the lysosomal enzyme α-GAL. This leads to the progressive accumulation of Gb3 in cells, causing multi-systemic effects. FD [...] Read more.
Fabry disease (FD) is an X-linked lysosomal storage disease, caused by mutations in the GLA gene on the X chromosome, resulting in a deficiency of the lysosomal enzyme α-GAL. This leads to the progressive accumulation of Gb3 in cells, causing multi-systemic effects. FD has been classified as a subgroup of autoinflammatory diseases. NF-κB is a family of ubiquitous and inducible transcription factors that play critical roles in inflammation, in which the p65/p50 heterodimer is the most abundant. The glucocorticoid receptor (GR) represents the physiological antagonists in the inflammation process. A novel spliced variant of p65, named p65 iso5, which can bind the dexamethasone, enhancing GR activity, has been found. This study investigates the potential role of p65 iso5 in the inflammation of subjects with FD. We evaluated in peripheral blood mononuclear cells (PBMCs), from over 100 FD patients, the p65 iso5 mRNA level, and the protein expression. The results showed significantly lower p65 iso5 mRNA and protein expression levels compared to controls. These findings, along with the ability of p65 iso5 to bind dexamethasone and the regulation of the glucocorticoid response in the opposite way of p65, strongly suggest the involvement of p65 iso5 in the inflammatory response in FD. Full article
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21 pages, 6149 KiB  
Article
Genome-Wide Characterization of Extrachromosomal Circular DNA in the Midgut of BmCPV-Infected Silkworms and Its Potential Role in Antiviral Responses
by Xinyu Tong, Chao Lei, Yilin Liu, Mei Yin, Huan Peng, Qunnan Qiu, Yongjie Feng, Xiaolong Hu, Chengliang Gong and Min Zhu
Int. J. Mol. Sci. 2025, 26(2), 818; https://doi.org/10.3390/ijms26020818 - 19 Jan 2025
Viewed by 1160
Abstract
Extrachromosomal circular DNAs (eccDNAs) has been found to be widespread and functional in various organisms. However, comparative analyses of pre- and post-infection of virus are rarely known. Herein, we investigated the changes in expression patterns of eccDNA following infection with Bombyx mori cytoplasmic [...] Read more.
Extrachromosomal circular DNAs (eccDNAs) has been found to be widespread and functional in various organisms. However, comparative analyses of pre- and post-infection of virus are rarely known. Herein, we investigated the changes in expression patterns of eccDNA following infection with Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) and explore the role of eccDNA in viral infection. Circle-seq was used to analyze eccDNAs in the midgut of BmCPV-infected and BmCPV-uninfected silkworms. A total of 5508 eccDNAs were identified, with sizes varying from 72 bp to 17 kb. Most of eccDNAs are between 100 to 1000 bp in size. EccDNA abundance in BmCPV-infected silkworms was significantly higher than in BmCPV-uninfected silkworms. GO and KEGG analysis of genes carried by eccDNAs reveals that most are involved in microtubule motor activity, phosphatidic acid binding, cAMP signaling pathway, and pancreatic secretion signaling pathways. Several eccDNAs contain sequences of the transcription factor SOX6, sem-2, sp8b, or Foxa2. Association analysis of eccDNA-mRNA/miRNA/circRNA revealed that some highly expressed genes are transcribed from relevant sequences of eccDNA and the transcription of protein coding genes influenced the frequency of eccDNA. BmCPV infection resulted in changes in the expression levels of six miRNAs, but no known miRNAs with altered expression levels due to changes in eccDNA abundance were identified. Moreover, it was found that 1287 and 924 sequences representing back-spliced junctions of circRNAs were shared by the junctions of eccDNAs in the BmCPV-infected and uninfected silkworms, respectively, and some eccDNAs loci were shared by circRNAs on Chromosomes 2, 7, 11, 14, and 24, suggesting some eccDNAs may exert its function by being transcribed into circRNAs. These findings suggest that BmCPV infection alter the expression pattern of eccDNAs, leading to changes in RNA transcription levels, which may play roles in regulating BmCPV replication. In the future, further experiments are needed to verify the association between eccDNA-mRNA/miRNA/circRNA and its function in BmCPV infection. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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13 pages, 1279 KiB  
Review
Circular RNA Formation and Degradation Are Not Directed by Universal Pathways
by Arvind Srinivasan, Emilia Mroczko-Młotek and Marzena Wojciechowska
Int. J. Mol. Sci. 2025, 26(2), 726; https://doi.org/10.3390/ijms26020726 - 16 Jan 2025
Cited by 4 | Viewed by 1792
Abstract
Circular RNAs (circRNAs) are a class of unique transcripts characterized by a covalently closed loop structure, which differentiates them from conventional linear RNAs. The formation of circRNAs occurs co-transcriptionally and post-transcriptionally through a distinct type of splicing known as back-splicing, which involves the [...] Read more.
Circular RNAs (circRNAs) are a class of unique transcripts characterized by a covalently closed loop structure, which differentiates them from conventional linear RNAs. The formation of circRNAs occurs co-transcriptionally and post-transcriptionally through a distinct type of splicing known as back-splicing, which involves the formation of a head-to-tail splice junction between a 5′ splice donor and an upstream 3′ splice acceptor. This process, along with exon skipping, intron retention, cryptic splice site utilization, and lariat-driven intron processing, results in the generation of three main types of circRNAs (exonic, intronic, and exonic–intronic) and their isoforms. The intricate biogenesis of circRNAs is regulated by the interplay of cis-regulatory elements and trans-acting factors, with intronic Alu repeats and RNA-binding proteins playing pivotal roles, at least in the formation of exonic circRNAs. Various hypotheses regarding pathways of circRNA turnover are forwarded, including endonucleolytic cleavage and exonuclease-mediated degradation; however, similarly to the inconclusive nature of circRNA biogenesis, the process of their degradation and the factors involved remain largely unclear. There is a knowledge gap regarding whether these processes are guided by universal pathways or whether each category of circRNAs requires special tools and particular mechanisms for their life cycles. Understanding these factors is pivotal for fully comprehending the biological significance of circRNAs. This review provides an overview of the various pathways involved in the biogenesis and degradation of different types of circRNAs and explores key factors that have beneficial or adverse effects on the formation and stability of these unique transcripts in higher eukaryotes. Full article
(This article belongs to the Section Molecular Biology)
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27 pages, 1958 KiB  
Review
Host RNA-Binding Proteins as Regulators of HIV-1 Replication
by Sebastian Giraldo-Ocampo, Fernando Valiente-Echeverría and Ricardo Soto-Rifo
Viruses 2025, 17(1), 43; https://doi.org/10.3390/v17010043 - 31 Dec 2024
Viewed by 1775
Abstract
RNA-binding proteins (RBPs) are cellular factors involved in every step of RNA metabolism. During HIV-1 infection, these proteins are key players in the fine-tuning of viral and host cellular and molecular pathways, including (but not limited to) viral entry, transcription, splicing, RNA modification, [...] Read more.
RNA-binding proteins (RBPs) are cellular factors involved in every step of RNA metabolism. During HIV-1 infection, these proteins are key players in the fine-tuning of viral and host cellular and molecular pathways, including (but not limited to) viral entry, transcription, splicing, RNA modification, translation, decay, assembly, and packaging, as well as the modulation of the antiviral response. Targeted studies have been of paramount importance in identifying and understanding the role of RNA-binding proteins that bind to HIV-1 RNAs. However, novel approaches aimed at identifying all the proteins bound to specific RNAs (RBPome), such as RNA interactome capture, have also contributed to expanding our understanding of the HIV-1 replication cycle, allowing the identification of RBPs with functions not only in viral RNA metabolism but also in cellular metabolism. Strikingly, several of the RBPs found through interactome capture are not canonical RBPs, meaning that they do not have conventional RNA-binding domains and are therefore not readily predicted as being RBPs. Further studies on the different cellular targets of HIV-1, such as subtypes of T cells or myeloid cells, or on the context (active replication versus reactivation from latency) are needed to fully elucidate the host RBPome bound to the viral RNA, which will allow researchers and clinicians to discover new therapeutic targets during active replication and provirus reactivation from latency. Full article
(This article belongs to the Special Issue Regulation of the Virus Lifecycle by Cellular RNA-Binding Proteins)
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15 pages, 879 KiB  
Review
DDX21 at the Nexus of RNA Metabolism, Cancer Oncogenesis, and Host–Virus Crosstalk: Decoding Its Biomarker Potential and Therapeutic Implications
by Yalan Xiao, Jiankun Fan, Zhigang Li and Yu Hou
Int. J. Mol. Sci. 2024, 25(24), 13581; https://doi.org/10.3390/ijms252413581 - 19 Dec 2024
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Abstract
DDX21, a member of the DEAD-box RNA helicase family, plays a pivotal role in various aspects of RNA metabolism, including ribosomal RNA (rRNA) processing, transcription, and translation. Its diverse functions in cancer progression and viral infections have attracted considerable attention. DDX21 exerts a [...] Read more.
DDX21, a member of the DEAD-box RNA helicase family, plays a pivotal role in various aspects of RNA metabolism, including ribosomal RNA (rRNA) processing, transcription, and translation. Its diverse functions in cancer progression and viral infections have attracted considerable attention. DDX21 exerts a pivotal function through ribosomal DNA (rDNA) transcription and rRNA processing. DDX21 is involved in different biological processes of mRNA transcription. It interacts with transcription factors, modulates RNA polymerase II elongation, binds R-loops to regulate transcription, and participates in alternative splicing. The elevated expression of DDX21 has been observed in most cancers, where it influences tumorigenesis by affecting ribosome biogenesis, transcription, genome stability, and cell cycle regulation. Additionally, DDX21 plays a key role in the antiviral defense of host by interacting with viral proteins to regulate essential stages of the infection process. This review provides a thorough examination of the biological functions of DDX21, its involvement in cancer progression and viral infections, and its potential as both a biomarker and a therapeutic target. Future studies should aim to clarify the specific mechanisms of the activity of DDX21, advance the development of targeted therapies, and assess its clinical relevance across various cancer types and stages. Full article
(This article belongs to the Section Molecular Oncology)
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