Jakub Dudzik, Paulina Czechowicz, Anna Więch-Walów, Jakub Sławski, James F Collawn, Rafal Bartoszewski
{"title":"PiRNAs, PiRNA-Like, and PIWI Proteins in Somatic Cells: From Genetic Regulation to Disease Mechanisms.","authors":"Jakub Dudzik, Paulina Czechowicz, Anna Więch-Walów, Jakub Sławski, James F Collawn, Rafal Bartoszewski","doi":"10.1002/wrna.70012","DOIUrl":"10.1002/wrna.70012","url":null,"abstract":"<p><p>PIWI-interacting RNAs (piRNAs) are small non-coding RNA molecules that were originally described as responsible for binding to PIWI proteins to silence transposons in the germline genome. Here we discuss their controversial influence in regulating gene expression in human somatic cells. Although their functions in human somatic cells remain controversial, current research has focused on their potential contribution to human diseases including cancers and cardiovascular diseases (CVDs). These small RNA molecules directly interact with PIWI proteins to form piRNA-induced silencing complexes (piRISC). These complexes regulate not only long non-coding RNAs (lncRNAs) but also mRNAs in their 3' untranslated region. The controversy in human somatic cells occurs because not all of the reports demonstrate a direct interaction between the small non-coding RNAs and the PIWI proteins and also whether these established complexes have silencing activities. Therefore, their importance in human physiology and pathology continues to remain controversial. Here we discuss the challenges and limitations that need to be addressed in order to establish and harness the potential of these ncRNAs in potential clinical applications. In this review, we distinguish those examples that have been shown to function as silencing complexes (piRNAs) from those that appear to be silencing complexes based only on their ability to bind to PIWI proteins (piRNA-like) in human somatic cells.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"16 2","pages":"e70012"},"PeriodicalIF":6.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Moh Egy Rahman Firdaus, Eliana Dukhno, Rupali Kapoor, Piotr Gerlach
{"title":"Two Birds With One Stone: RNA Virus Strategies to Manipulate G3BP1 and Other Stress Granule Components.","authors":"Moh Egy Rahman Firdaus, Eliana Dukhno, Rupali Kapoor, Piotr Gerlach","doi":"10.1002/wrna.70005","DOIUrl":"10.1002/wrna.70005","url":null,"abstract":"<p><p>Stress granules (SGs) are membrane-less organelles forming in the cytoplasm in response to various types of stress, including viral infection. SGs and SG-associated proteins can play either a proviral role, by facilitating viral replication, or an antiviral role, by limiting the translation capacity, sequestering viral RNA, or contributing to the innate immune response of the cell. Consequently, viruses frequently target stress granules while counteracting cellular translation shut-off and the antiviral response. One strategy is to sequester SG components, not only to impair their assembly but also to repurpose and incorporate them into viral replication sites. G3BP1 is a key SG protein, driving its nucleation through protein-protein and protein-RNA interactions. Many cellular proteins, including other SG components, interact with G3BP1 via their ΦxFG motifs. Notably, SARS-CoV N proteins and alphaviral nsP3 proteins contain similar motifs, allowing them to compete for G3BP1. Several SG proteins have been shown to interact with the flaviviral capsid protein, which is primarily responsible for anchoring the viral genome inside the virion. There are also numerous examples of structured elements within coronaviral and flaviviral RNAs recruiting or sponging SG proteins. Despite these insights, the structural and biochemical details of SG-virus interactions remain largely unexplored and are known only for a handful of cases. Exploring their molecular relevance for infection and discovering new examples of direct SG-virus contacts is highly important, as advances in this area will open new possibilities for the design of targeted therapies and potentially broad-spectrum antivirals.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"16 2","pages":"e70005"},"PeriodicalIF":6.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Metabolism Meets Translation: Dietary and Metabolic Influences on tRNA Modifications and Codon Biased Translation.","authors":"Sherif Rashad, Aseel Marahleh","doi":"10.1002/wrna.70011","DOIUrl":"10.1002/wrna.70011","url":null,"abstract":"<p><p>Transfer RNA (tRNA) is not merely a passive carrier of amino acids, but an active regulator of mRNA translation controlling codon bias and optimality. The synthesis of various tRNA modifications is regulated by many \"writer\" enzymes, which utilize substrates from metabolic pathways or dietary sources. Metabolic and bioenergetic pathways, such as one-carbon (1C) metabolism and the tricarboxylic acid (TCA) cycle produce essential substrates for tRNA modifications synthesis, such as S-Adenosyl methionine (SAM), sulfur species, and α-ketoglutarate (α-KG). The activity of these metabolic pathways can directly impact codon decoding and translation via regulating tRNA modifications levels. In this review, we discuss the complex interactions between diet, metabolism, tRNA modifications, and mRNA translation. We discuss how nutrient availability, bioenergetics, and intermediates of metabolic pathways, modulate the tRNA modification landscape to fine-tune protein synthesis. Moreover, we highlight how dysregulation of these metabolic-tRNA interactions contributes to disease pathogenesis, including cancer, metabolic disorders, and neurodegenerative diseases. We also discuss the new emerging field of GlycoRNA biology drawing parallels from glycobiology and metabolic diseases to guide future directions in this area. Throughout our discussion, we highlight the links between specific modifications, their metabolic/dietary precursors, and various diseases, emphasizing the importance of a metabolism-centric tRNA view in understanding many pathologies. Future research should focus on uncovering the interplay between metabolism and tRNA in specific cellular and disease contexts. Addressing these gaps will guide new research into novel disease interventions.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"16 2","pages":"e70011"},"PeriodicalIF":6.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11928779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bence György Gombás, Orsolya Németh-Szatmári, Bence Nagy-Mikó, Zoltán Villányi
{"title":"Role of Assemblysomes in Cellular Stress Responses.","authors":"Bence György Gombás, Orsolya Németh-Szatmári, Bence Nagy-Mikó, Zoltán Villányi","doi":"10.1002/wrna.70009","DOIUrl":"10.1002/wrna.70009","url":null,"abstract":"<p><p>Assemblysomes are recently discovered intracellular RNA-protein complexes that play important roles in cellular stress response, regulation of gene expression, and also in co-translational protein assembly. In this review, a wide spectrum overview of assemblysomes is provided, including their discovery, mechanism of action, characteristics, and potential applications in several fields. Assemblysomes are distinct liquid-liquid phase-separated condensates; they have certain unique properties differentiating them from other cellular granules. They are composed of ribosome-nascent protein chain complexes and are resistant to cycloheximide and EDTA. The discovery and observation of intracellular condensates, like assemblysomes, have further expanded our knowledge of cellular stress response mechanisms, particularly in DNA repair processes and defense against proteotoxicity. Ribosome profiling experiments and next-generation sequencing of cDNA libraries extracted from EDTA-resistant pellets-of ultracentrifuged cell lysates-have shed light on the composition and dynamics of assemblysomes, revealing their role as repositories for pre-made stress-responsive ribosome-nascent chain complexes. This review gives an exploration of assemblysomes' potential clinical applications from multiple aspects, including their usefulness as diagnostic biomarkers for chemotherapy resistance and their implications in cancer therapy. In addition, in this overview, we raise some theoretical ideas of industrial and agricultural applications connected to these membraneless organelles. However, we see several challenges. On one hand, we need to understand the complexity of assemblysomes' multiple functions and regulations; on the other hand, it is essential to bridge the gap between fundamental research and practical applications. Overall, assemblysome research can be perceived as a promising upcomer in the improvement of biomedical settings as well as those connected to agricultural and industrial aspects.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"16 2","pages":"e70009"},"PeriodicalIF":6.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Intron-Derived Lariat RNAs Go Stable.","authors":"Dan Liao, Binglian Zheng","doi":"10.1002/wrna.70006","DOIUrl":"10.1002/wrna.70006","url":null,"abstract":"<p><p>During pre-mRNA splicing, introns are removed by the spliceosome, and the flanking exons are ligated to form mature mRNA, which is subsequently translated into protein. Traditionally, intronic RNAs have been regarded as \"junk\", presumed to be degraded for nucleotide turnover. Notably, after debranching, some linearized lariat RNAs can be further processed into snoRNAs, miRNAs, and other long non-coding RNAs. However, recent studies have shown that many intron-derived lariat RNAs can escape degradation and remain stable across various eukaryotic organisms, indicating they may play significant roles in cellular processes. Moreover, these naturally retained lariat RNAs are frequently observed in circular forms in vivo, suggesting that their linear tails are highly susceptible to degradation. This highlights lariat RNAs as an important source of circular RNAs. Furthermore, many lariat-derived circRNAs have been detected in the cytoplasm, implying active nuclear export and potential roles in cytoplasmic processes. In this review, we provide an overview of the life cycle of intron-derived lariat RNAs, focusing on their biogenesis, degradation, and retention. We also discuss the mechanisms that enable their resistance to degradation and the biological functions of stable lariat RNAs, shedding light on these seemingly \"nonsense\" yet inevitably produced non-coding intronic RNAs.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"16 2","pages":"e70006"},"PeriodicalIF":6.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Functional Landscape of hnRNPA3 in Disease Pathogenesis.","authors":"Fang Chen, Genghan Li, Shuang Fu, Jihong Zhang","doi":"10.1002/wrna.70010","DOIUrl":"10.1002/wrna.70010","url":null,"abstract":"<p><p>The heterogeneous nuclear ribonucleic acid protein family participates in various intracellular reactions, such as RNA splicing, transport, DNA repair, cellular signal transduction, and gene expression regulation, and is involved in various disease processes. As a late-discovered member, heterogeneous nuclear ribonucleoprotein A3 has received increasing attention, but its main physiological functions and exact mechanisms involved in disease processes have not yet reached a consensus. In this review, we summarize the function of heterogeneous nuclear ribonucleoprotein A3 and the literature on its role in neurodegenerative and metabolic diseases, as well as in various tumors, to explore the applicability of heterogeneous nuclear ribonucleoprotein A3 as a therapeutic target and prognostic indicator.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"16 2","pages":"e70010"},"PeriodicalIF":6.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Syed Wasifa Qadri, Nisa Manzoor Shah, Ravi S Muddashetty
{"title":"Epitranscriptome-Mediated Regulation of Neuronal Translation.","authors":"Syed Wasifa Qadri, Nisa Manzoor Shah, Ravi S Muddashetty","doi":"10.1002/wrna.70004","DOIUrl":"10.1002/wrna.70004","url":null,"abstract":"<p><p>Epitranscriptomic modification of RNA is an important layer of regulation for gene expression. RNA modifications come in many flavors and generate a complex tapestry of a regulatory network. Here, we focus on two major RNA modifications, one on rRNA (2'O Methylation) and another on mRNA (N<sup>6</sup>-Methyladenosine [m<sup>6</sup>A]) and their impact on translation. The 2'O methyl group addition on the ribose sugar of rRNA plays a critical role in RNA folding, ribosome assembly, and its interaction with many RNA binding proteins. Differential methylation of these sites contributes to ribosome heterogeneity and generates potential \"specialized ribosomes.\" Specialized ribosomes are proposed to play a variety of important roles in maintaining pluripotency, lineage specification, and compartmentalized and activity-mediated translation in neurons. The m<sup>6</sup>A modification, on the other hand, determines the stability, transport, and translation of subclasses of mRNA. The dynamic nature of m<sup>6</sup>A owing to the localization and activity of its writers, readers, and erasers makes it a powerful tool for spatiotemporal regulation of translation. While substantial information has accumulated on the nature and abundance of these modifications, their functional consequences are still understudied. In this article, we review the literature constructing the body of our understanding of these two modifications and their outcome on the regulation of translation in general and their impact on the nervous system in particular. We also explore the possibility of how these modifications may collaborate in modulating translation and provoke the thought to integrate the functions of multiple epitranscriptome modifications.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"16 1","pages":"e70004"},"PeriodicalIF":6.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katarzyna Grelewska-Nowotko, Ahmed Eisa Elhag, Tomasz Wojciech Turowski
{"title":"Transcription Kinetics in the Coronavirus Life Cycle.","authors":"Katarzyna Grelewska-Nowotko, Ahmed Eisa Elhag, Tomasz Wojciech Turowski","doi":"10.1002/wrna.70000","DOIUrl":"10.1002/wrna.70000","url":null,"abstract":"<p><p>Coronaviruses utilize a positive-sense single-strand RNA, functioning simultaneously as mRNA and the genome. An RNA-dependent RNA polymerase (RdRP) plays a dual role in transcribing genes and replicating the genome, making RdRP a critical target in therapies against coronaviruses. This review explores recent advancements in understanding the coronavirus transcription machinery, discusses it within virus infection context, and incorporates kinetic considerations on RdRP activity. We also address steric limitations in coronavirus replication, particularly during early infection phases, and outline hypothesis regarding translation-transcription conflicts, postulating the existence of mechanisms that resolve these issues. In cells infected by coronaviruses, abundant structural proteins are synthesized from subgenomic RNA fragments (sgRNAs) produced via discontinuous transcription. During elongation, RdRP can skip large sections of the viral genome, resulting in the creation of shorter sgRNAs that reflects the stoichiometry of viral structural proteins. Although the precise mechanism of discontinuous transcription remains unknown, we discuss recent hypotheses involving long-distance RNA-RNA interactions, helicase-mediated RdRP backtracking, dissociation and reassociation of RdRP, and RdRP dimerization.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"16 1","pages":"e70000"},"PeriodicalIF":6.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11701415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hypothesis for Molecular Evolution in the Pre-Cellular Stage of the Origin of Life.","authors":"Yong Wang, Yiling Du","doi":"10.1002/wrna.70001","DOIUrl":"10.1002/wrna.70001","url":null,"abstract":"<p><p>Life was originated from inorganic world and had experienced a long period of evolution in about 3.8 billion years. The time for emergence of the pioneer creations on Earth is debatable nowadays, and how the scenario for the prebiotic molecular interactions is still mysterious. Before the spreading of cellular organisms, chemical evolution was perhaps prevailing for millions of years, in which inorganic biosynthesis was ultimately replaced by biochemical reactions. Understanding the major molecular players and their interactions toward cellular life is fundamental for current medical science and extraterrestrial life exploration. In this review, we propose a road map for the primordial molecular evolution in early Earth, which probably occurred adjacent to hydrothermal vents with a strong gradient of organic molecules, temperature, and metal contents. Natural selection of the macromolecules with strong secondary structures and catalytic centers is associated with decreasing of overall entropy of the biopolymers. Our review may shed lights into the important selection of gene-coding RNA with secondary structures from large amounts of random biopolymers and formation of ancient ribosomes with biological machines supporting the basic life processes. Integration of the free environmental ribosomes by the early cellular life as symbiotic molecular machines is probably the earliest symbiosis on Earth.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"16 1","pages":"e70001"},"PeriodicalIF":6.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Unusual Role of Ribonuclease L in Innate Immunity.","authors":"Agnes Karasik, Nicholas R Guydosh","doi":"10.1002/wrna.1878","DOIUrl":"10.1002/wrna.1878","url":null,"abstract":"<p><p>Ribonuclease L is an endonuclease that is activated as part of the dsRNA-driven innate immune response. Active RNase L cleaves pathogenic RNAs as a way to eliminate infections. However, there are additional and unexpected ways that RNase L causes changes in the host that promote an immune response and contribute to its role in host defense. Central to these unconventional mechanisms is the observation that RNase L also degrades the mRNA of the host. In turn, mRNA fragments that RNase L generates can be translated. This causes activation of a ribosome collision sensor that leads to downstream signaling and cell death. Additionally, the liberation of RNA binding proteins after RNA decay appears to affect gene expression. In this review, we discuss these and other recent advances that focus on novel and unusual ways RNase L contributes to innate immunity.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"15 6","pages":"e1878"},"PeriodicalIF":6.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11672174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}