Katarzyna Grelewska-Nowotko, Ahmed Eisa Elhag, Tomasz Wojciech Turowski
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.
{"title":"Transcription Kinetics in the Coronavirus Life Cycle.","authors":"Katarzyna Grelewska-Nowotko, Ahmed Eisa Elhag, Tomasz Wojciech Turowski","doi":"10.1002/wrna.70000","DOIUrl":"https://doi.org/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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"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":"https://doi.org/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}
Izabela Broniarek, Daria Niewiadomska, Krzysztof Sobczak
Repeat expansion disorders (REDs) encompass over 50 inherited neurological disorders and are characterized by the expansion of short tandem nucleotide repeats beyond a specific repeat length. Particularly intriguing among these are multiple fragile X-associated disorders (FXds), which arise from an expansion of CGG repeats in the 5' untranslated region of the FMR1 gene. Despite arising from repeat expansions in the same gene, the clinical manifestations of FXds vary widely, encompassing developmental delays, parkinsonism, dementia, and an increased risk of infertility. FXds also exhibit molecular mechanisms observed in other REDs, that is, gene- and protein-loss-of-function and RNA- and protein-gain-of-function. The heterogeneity of phenotypes and pathomechanisms in FXds results from the different lengths of the CGG tract. As the number of repeats increases, the structures formed by RNA and DNA fragments containing CGG repeats change significantly, contributing to the diversity of FXd phenotypes and mechanisms. In this review, we discuss the role of RNA and DNA structures formed by expanded CGG repeats in driving FXd pathogenesis and how the genetic instability of CGG repeats is mediated by the complex interplay between transcription, DNA replication, and repair. We also discuss therapeutic strategies, including small molecules, antisense oligonucleotides, and CRISPR-Cas systems, that target toxic RNA and DNA involved in the development of FXds.
重复扩增性疾病(REDs)包括 50 多种遗传性神经系统疾病,其特征是短串联核苷酸重复序列的扩增超过了特定的重复长度。其中尤为引人关注的是多发性脆性 X 相关疾病(FXds),它是由 FMR1 基因 5' 非翻译区的 CGG 重复序列扩增引起的。尽管脆性 X 相关疾病是由同一基因的重复扩增引起的,但其临床表现却千差万别,包括发育迟缓、帕金森氏症、痴呆症和不孕不育风险增加。FXds 还表现出在其他 REDs 中观察到的分子机制,即基因和蛋白功能缺失以及 RNA 和蛋白功能增益。FXds 表型和病理机制的异质性源于 CGG 道的不同长度。随着重复序列数量的增加,含有 CGG 重复序列的 RNA 和 DNA 片段所形成的结构也会发生显著变化,从而导致 FXd 表型和机制的多样性。在这篇综述中,我们将讨论由扩展的 CGG 重复序列形成的 RNA 和 DNA 结构在驱动 FXd 发病机制中的作用,以及 CGG 重复序列的遗传不稳定性是如何通过转录、DNA 复制和修复之间复杂的相互作用来介导的。我们还讨论了针对参与 FXds 发病的有毒 RNA 和 DNA 的治疗策略,包括小分子、反义寡核苷酸和 CRISPR-Cas 系统。
{"title":"Contribution of DNA/RNA Structures Formed by Expanded CGG/CCG Repeats Within the FMR1 Locus in the Pathogenesis of Fragile X-Associated Disorders.","authors":"Izabela Broniarek, Daria Niewiadomska, Krzysztof Sobczak","doi":"10.1002/wrna.1874","DOIUrl":"https://doi.org/10.1002/wrna.1874","url":null,"abstract":"<p><p>Repeat expansion disorders (REDs) encompass over 50 inherited neurological disorders and are characterized by the expansion of short tandem nucleotide repeats beyond a specific repeat length. Particularly intriguing among these are multiple fragile X-associated disorders (FXds), which arise from an expansion of CGG repeats in the 5' untranslated region of the FMR1 gene. Despite arising from repeat expansions in the same gene, the clinical manifestations of FXds vary widely, encompassing developmental delays, parkinsonism, dementia, and an increased risk of infertility. FXds also exhibit molecular mechanisms observed in other REDs, that is, gene- and protein-loss-of-function and RNA- and protein-gain-of-function. The heterogeneity of phenotypes and pathomechanisms in FXds results from the different lengths of the CGG tract. As the number of repeats increases, the structures formed by RNA and DNA fragments containing CGG repeats change significantly, contributing to the diversity of FXd phenotypes and mechanisms. In this review, we discuss the role of RNA and DNA structures formed by expanded CGG repeats in driving FXd pathogenesis and how the genetic instability of CGG repeats is mediated by the complex interplay between transcription, DNA replication, and repair. We also discuss therapeutic strategies, including small molecules, antisense oligonucleotides, and CRISPR-Cas systems, that target toxic RNA and DNA involved in the development of FXds.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"15 6","pages":"e1874"},"PeriodicalIF":6.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629053","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}
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.
{"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}
The RNA recognition motif (RRM) is the most common RNA binding domain found in the human proteome. RRM domains provide RNA-binding proteins with sequence specific RNA recognition allowing them to participate in RNA-centric processes such as mRNA maturation, translation initiation, splicing, and RNA degradation. They are drivers of various diseases through overexpression or mutation, making them attractive therapeutic targets and addressing these proteins through their RRM domains with chemical compounds is gaining ever more attention. However, it is still very challenging to find selective and potent RNA-competitors due to the small size of the domain and high structural conservation of its RNA binding interface. Despite these challenges, a selection of compounds has been reported for several RRM containing proteins, but often with limited biophysical evidence and low selectivity. A solution to selectively targeting RRM domains might be through avoiding the RNA-binding surface altogether, but rather look for composite pockets formed with other proteins or for protein-protein interaction sites that regulate the target's activity but are less conserved. Alternative modalities, such as oligonucleotides, peptides, and molecular glues, are exciting new approaches to address these challenging targets and achieve the goal of therapeutic intervention at the RNA regulatory level.
{"title":"Challenges in Therapeutically Targeting the RNA-Recognition Motif.","authors":"Stefan Schmeing, Peter 't Hart","doi":"10.1002/wrna.1877","DOIUrl":"10.1002/wrna.1877","url":null,"abstract":"<p><p>The RNA recognition motif (RRM) is the most common RNA binding domain found in the human proteome. RRM domains provide RNA-binding proteins with sequence specific RNA recognition allowing them to participate in RNA-centric processes such as mRNA maturation, translation initiation, splicing, and RNA degradation. They are drivers of various diseases through overexpression or mutation, making them attractive therapeutic targets and addressing these proteins through their RRM domains with chemical compounds is gaining ever more attention. However, it is still very challenging to find selective and potent RNA-competitors due to the small size of the domain and high structural conservation of its RNA binding interface. Despite these challenges, a selection of compounds has been reported for several RRM containing proteins, but often with limited biophysical evidence and low selectivity. A solution to selectively targeting RRM domains might be through avoiding the RNA-binding surface altogether, but rather look for composite pockets formed with other proteins or for protein-protein interaction sites that regulate the target's activity but are less conserved. Alternative modalities, such as oligonucleotides, peptides, and molecular glues, are exciting new approaches to address these challenging targets and achieve the goal of therapeutic intervention at the RNA regulatory level.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"15 6","pages":"e1877"},"PeriodicalIF":6.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819417","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}
RNA processing involves steps such as capping, splicing, polyadenylation, modification, and nuclear export. These steps are essential for transforming genetic information in DNA into proteins and contribute to RNA diversity and complexity. Many biochemical methods have been developed to profile and quantify RNAs, as well as to identify the interactions between RNAs and RNA-binding proteins (RBPs), especially when coupled with high-throughput sequencing technologies. With the rapid accumulation of diverse data, it is crucial to develop computational methods to convert the big data into biological knowledge. In particular, machine learning and deep learning models are commonly utilized to learn the rules or codes governing the transformation from DNA sequences to intriguing RNAs based on manually designed or automatically extracted features. When precise enough, the RNA codes can be incredibly useful for predicting RNA products, decoding the molecular mechanisms, forecasting the impact of disease variants on RNA processing events, and identifying driver mutations. In this review, we systematically summarize the biochemical and computational methods for deciphering five important RNA codes related to alternative splicing, alternative polyadenylation, RNA localization, RNA modifications, and RBP binding. For each code, we review the main types of experimental methods used to generate training data, as well as the key features, strategic model structures, and advantages of representative tools. We also discuss the challenges encountered in developing predictive models using large language models and extensive domain knowledge. Additionally, we highlight useful resources and propose ways to improve computational tools for studying RNA codes.
{"title":"Integrated Biochemical and Computational Methods for Deciphering RNA-Processing Codes.","authors":"Chen Du, Weiliang Fan, Yu Zhou","doi":"10.1002/wrna.1875","DOIUrl":"https://doi.org/10.1002/wrna.1875","url":null,"abstract":"<p><p>RNA processing involves steps such as capping, splicing, polyadenylation, modification, and nuclear export. These steps are essential for transforming genetic information in DNA into proteins and contribute to RNA diversity and complexity. Many biochemical methods have been developed to profile and quantify RNAs, as well as to identify the interactions between RNAs and RNA-binding proteins (RBPs), especially when coupled with high-throughput sequencing technologies. With the rapid accumulation of diverse data, it is crucial to develop computational methods to convert the big data into biological knowledge. In particular, machine learning and deep learning models are commonly utilized to learn the rules or codes governing the transformation from DNA sequences to intriguing RNAs based on manually designed or automatically extracted features. When precise enough, the RNA codes can be incredibly useful for predicting RNA products, decoding the molecular mechanisms, forecasting the impact of disease variants on RNA processing events, and identifying driver mutations. In this review, we systematically summarize the biochemical and computational methods for deciphering five important RNA codes related to alternative splicing, alternative polyadenylation, RNA localization, RNA modifications, and RBP binding. For each code, we review the main types of experimental methods used to generate training data, as well as the key features, strategic model structures, and advantages of representative tools. We also discuss the challenges encountered in developing predictive models using large language models and extensive domain knowledge. Additionally, we highlight useful resources and propose ways to improve computational tools for studying RNA codes.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"15 6","pages":"e1875"},"PeriodicalIF":6.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629055","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}
Michal H Kolář, Hugo McGrath, Felipe C Nepomuceno, Michaela Černeková
All proteins in living organisms are produced in ribosomes that facilitate the translation of genetic information into a sequence of amino acid residues. During translation, the ribosome undergoes initiation, elongation, termination, and recycling. In fact, peptide bonds are formed only during the elongation phase, which comprises periodic association of transfer RNAs and multiple auxiliary proteins with the ribosome and the addition of an amino acid to the nascent polypeptide one at a time. The protein spends a considerable amount of time attached to the ribosome. Here, we conceptually divide this portion of the protein lifetime into three stages. We define each stage on the basis of the position of the N-terminus of the nascent polypeptide within the ribosome exit tunnel and the context of the catalytic center. We argue that nascent polypeptides experience a variety of forces that determine how they translocate through the tunnel and interact with the tunnel walls. We review current knowledge about nascent polypeptide translocation and identify several white spots in our understanding of the birth of proteins.
生物体内的所有蛋白质都是在核糖体中产生的,核糖体可将遗传信息翻译成氨基酸残基序列。在翻译过程中,核糖体经历了启动、延伸、终止和再循环。事实上,只有在延伸阶段才会形成肽键,该阶段包括转移核糖核酸和多种辅助蛋白质与核糖体的周期性结合,以及在新生多肽中一次添加一个氨基酸。蛋白质在核糖体上附着的时间相当长。在这里,我们从概念上将这部分蛋白质的生命周期分为三个阶段。我们根据新生多肽 N 端在核糖体出口隧道中的位置和催化中心的环境来定义每个阶段。我们认为,新生多肽会经历各种作用力,这些作用力决定了它们如何通过隧道并与隧道壁相互作用。我们回顾了目前有关新生多肽转运的知识,并指出了我们对蛋白质诞生的理解中的几个白点。
{"title":"Three Stages of Nascent Protein Translocation Through the Ribosome Exit Tunnel.","authors":"Michal H Kolář, Hugo McGrath, Felipe C Nepomuceno, Michaela Černeková","doi":"10.1002/wrna.1873","DOIUrl":"https://doi.org/10.1002/wrna.1873","url":null,"abstract":"<p><p>All proteins in living organisms are produced in ribosomes that facilitate the translation of genetic information into a sequence of amino acid residues. During translation, the ribosome undergoes initiation, elongation, termination, and recycling. In fact, peptide bonds are formed only during the elongation phase, which comprises periodic association of transfer RNAs and multiple auxiliary proteins with the ribosome and the addition of an amino acid to the nascent polypeptide one at a time. The protein spends a considerable amount of time attached to the ribosome. Here, we conceptually divide this portion of the protein lifetime into three stages. We define each stage on the basis of the position of the N-terminus of the nascent polypeptide within the ribosome exit tunnel and the context of the catalytic center. We argue that nascent polypeptides experience a variety of forces that determine how they translocate through the tunnel and interact with the tunnel walls. We review current knowledge about nascent polypeptide translocation and identify several white spots in our understanding of the birth of proteins.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"15 6","pages":"e1873"},"PeriodicalIF":6.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576877","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}
Circular RNAs (circRNAs) are closed RNA loops present in humans and other organisms. Various circRNAs have an essential role in diseases, including cancer. Cells can release circRNAs into the extracellular space of adjacent biofluids and can be present in extracellular vesicles. Due to their circular nature, extracellular circRNAs (excircRNAs) are more stable than their linear counterparts and are abundant in many biofluids, such as blood plasma and urine. circRNAs' link with disease suggests their extracellular counterparts have high biomarker potential. However, circRNAs and the extracellular space are challenging research domains, as they consist of complex biological systems plagued with nomenclature issues and a wide variety of protocols with different advantages and disadvantages. Here, we summarize what is known about excircRNAs, the current challenges in the field, and what is needed to improve extracellular circRNA research.
{"title":"Current Understandings and Open Hypotheses on Extracellular Circular RNAs.","authors":"Jasper Verwilt, Marieke Vromman","doi":"10.1002/wrna.1872","DOIUrl":"10.1002/wrna.1872","url":null,"abstract":"<p><p>Circular RNAs (circRNAs) are closed RNA loops present in humans and other organisms. Various circRNAs have an essential role in diseases, including cancer. Cells can release circRNAs into the extracellular space of adjacent biofluids and can be present in extracellular vesicles. Due to their circular nature, extracellular circRNAs (excircRNAs) are more stable than their linear counterparts and are abundant in many biofluids, such as blood plasma and urine. circRNAs' link with disease suggests their extracellular counterparts have high biomarker potential. However, circRNAs and the extracellular space are challenging research domains, as they consist of complex biological systems plagued with nomenclature issues and a wide variety of protocols with different advantages and disadvantages. Here, we summarize what is known about excircRNAs, the current challenges in the field, and what is needed to improve extracellular circRNA research.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"15 6","pages":"e1872"},"PeriodicalIF":6.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591813","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}
Satya P Sharma, Mamta Chawla-Sarkar, Rajat Sandhir, Dipanjan Dutta
Influenza viruses (types A, B, C, and D) belong to the family orthomyxoviridae. Out of all the influenza types, influenza A virus (IAV) causes human pandemic outbreaks. Its pandemic potential is predominantly attributed to the genetic reassortment favored by a broad spectrum of host species that could lead to an antigenic shift along with a high rate of mutations in its genome, presenting a possibility of subtypes with heightened pathogenesis and virulence in humans (antigenic drift). In addition to antigenic shift and drift, there are several other inherent properties of its viral RNA species (vRNA, vmRNA, and cRNA) that significantly contribute to the success of specific stages of viral infection. In this review, we compile the key features of IAV RNA, such as sequence motifs and secondary structures, their functional significance in the infection cycle, and their overall impact on the virus's adaptive and evolutionary fitness. Because many of these motifs and folds are conserved, we also assess the existing antiviral approaches focused on targeting IAV RNA. This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.
{"title":"Decoding the role of RNA sequences and their interactions in influenza A virus infection and adaptation.","authors":"Satya P Sharma, Mamta Chawla-Sarkar, Rajat Sandhir, Dipanjan Dutta","doi":"10.1002/wrna.1871","DOIUrl":"https://doi.org/10.1002/wrna.1871","url":null,"abstract":"<p><p>Influenza viruses (types A, B, C, and D) belong to the family orthomyxoviridae. Out of all the influenza types, influenza A virus (IAV) causes human pandemic outbreaks. Its pandemic potential is predominantly attributed to the genetic reassortment favored by a broad spectrum of host species that could lead to an antigenic shift along with a high rate of mutations in its genome, presenting a possibility of subtypes with heightened pathogenesis and virulence in humans (antigenic drift). In addition to antigenic shift and drift, there are several other inherent properties of its viral RNA species (vRNA, vmRNA, and cRNA) that significantly contribute to the success of specific stages of viral infection. In this review, we compile the key features of IAV RNA, such as sequence motifs and secondary structures, their functional significance in the infection cycle, and their overall impact on the virus's adaptive and evolutionary fitness. Because many of these motifs and folds are conserved, we also assess the existing antiviral approaches focused on targeting IAV RNA. This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"15 6","pages":"e1871"},"PeriodicalIF":6.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583928","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}
Ribonucleic acid (RNA) undergoes dynamic changes in its structure and function under various intracellular and extracellular conditions over time. However, there is a lack of research on the concept of the RNA age to describe its diverse fates. This study proposes a definition of RNA age to address this issue. RNA age was defined as a sequence of numbers wherein the elements in the sequence were the nucleotide ages of the ribonucleotide residues in the RNA. Mean nucleotide age was used to represent RNA age. This definition describes the temporal properties of RNAs that have undergone diverse life histories and reflects the dynamic state of each ribonucleotide residue, which can be expressed mathematically. Notably, events (including base insertions, base deletions, and base substitutions) are likely to cause RNA to become younger or older when using mean nucleotide ages to represent the RNA age. Although information, including the presence of added markers in RNA, chemical modification structure of the RNA, and the excision of introns in the mRNA in cells, may provide a basis for identifying RNA age, little is known about determining the RNA age of extracellular RNA in the wild. Nonetheless, we believe that RNA age has an important relationship with the diverse biological properties of RNA under intracellular and extracellular conditions. Therefore, our proposed definition of RNA age offers new perspectives for studying dynamic changes in RNA function, RNA aging, ancient RNA, environmental RNA, and the ages of other biomolecules.
{"title":"The Definition of RNA Age Related to RNA Sequence Changes.","authors":"Zhongneng Xu, Shuichi Asakawa","doi":"10.1002/wrna.1876","DOIUrl":"https://doi.org/10.1002/wrna.1876","url":null,"abstract":"<p><p>Ribonucleic acid (RNA) undergoes dynamic changes in its structure and function under various intracellular and extracellular conditions over time. However, there is a lack of research on the concept of the RNA age to describe its diverse fates. This study proposes a definition of RNA age to address this issue. RNA age was defined as a sequence of numbers wherein the elements in the sequence were the nucleotide ages of the ribonucleotide residues in the RNA. Mean nucleotide age was used to represent RNA age. This definition describes the temporal properties of RNAs that have undergone diverse life histories and reflects the dynamic state of each ribonucleotide residue, which can be expressed mathematically. Notably, events (including base insertions, base deletions, and base substitutions) are likely to cause RNA to become younger or older when using mean nucleotide ages to represent the RNA age. Although information, including the presence of added markers in RNA, chemical modification structure of the RNA, and the excision of introns in the mRNA in cells, may provide a basis for identifying RNA age, little is known about determining the RNA age of extracellular RNA in the wild. Nonetheless, we believe that RNA age has an important relationship with the diverse biological properties of RNA under intracellular and extracellular conditions. Therefore, our proposed definition of RNA age offers new perspectives for studying dynamic changes in RNA function, RNA aging, ancient RNA, environmental RNA, and the ages of other biomolecules.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":"15 6","pages":"e1876"},"PeriodicalIF":6.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772813","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}