Pub Date : 2024-06-06DOI: 10.3389/frnar.2024.1419979
S. Choudhury, Anand Singh Rathore, G. Raghava
Long non-coding RNAs (lncRNAs) play a vital role in biological processes, and their dysfunctions lead to a wide range of diseases. Due to advancements in sequencing technology, more than 20,000 lncRNA transcripts have been identified in humans, almost equivalent to coding transcripts. One crucial aspect in annotating lncRNA function is predicting their subcellular localization, which often determines their functional roles within cells. This review aims to cover the experimental techniques, databases, and in silico tools developed for identifying subcellular localization. Firstly, we discuss the experimental methods employed to determine the subcellular localization of lncRNAs. These techniques provide valuable insights into the precise cellular compartments where lncRNAs reside. Secondly, we explore the available computational resources and databases contributing to our understanding of lncRNAs, including information on their subcellular localization. These computational methods utilize algorithms and machine learning approaches to predict lncRNA subcellular locations using sequence and structural features. Lastly, we discuss the limitations of existing methodologies, future challenges, and potential applications of subcellular localization prediction for lncRNAs. We highlight the need for further advancements in computational methods and experimental validation to enhance the accuracy and reliability of subcellular localization predictions. To support the scientific community, we have developed a platform called LncInfo, which offers comprehensive information on lncRNAs, including their subcellular localization. This platform aims to consolidate and provide accessible resources to researchers studying lncRNAs and their functional roles (http://webs.iiitd.edu.in/raghava/lncinfo).
{"title":"Compilation of resources on subcellular localization of lncRNA","authors":"S. Choudhury, Anand Singh Rathore, G. Raghava","doi":"10.3389/frnar.2024.1419979","DOIUrl":"https://doi.org/10.3389/frnar.2024.1419979","url":null,"abstract":"Long non-coding RNAs (lncRNAs) play a vital role in biological processes, and their dysfunctions lead to a wide range of diseases. Due to advancements in sequencing technology, more than 20,000 lncRNA transcripts have been identified in humans, almost equivalent to coding transcripts. One crucial aspect in annotating lncRNA function is predicting their subcellular localization, which often determines their functional roles within cells. This review aims to cover the experimental techniques, databases, and in silico tools developed for identifying subcellular localization. Firstly, we discuss the experimental methods employed to determine the subcellular localization of lncRNAs. These techniques provide valuable insights into the precise cellular compartments where lncRNAs reside. Secondly, we explore the available computational resources and databases contributing to our understanding of lncRNAs, including information on their subcellular localization. These computational methods utilize algorithms and machine learning approaches to predict lncRNA subcellular locations using sequence and structural features. Lastly, we discuss the limitations of existing methodologies, future challenges, and potential applications of subcellular localization prediction for lncRNAs. We highlight the need for further advancements in computational methods and experimental validation to enhance the accuracy and reliability of subcellular localization predictions. To support the scientific community, we have developed a platform called LncInfo, which offers comprehensive information on lncRNAs, including their subcellular localization. This platform aims to consolidate and provide accessible resources to researchers studying lncRNAs and their functional roles (http://webs.iiitd.edu.in/raghava/lncinfo).","PeriodicalId":73105,"journal":{"name":"Frontiers in RNA research","volume":"29 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141378820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.3389/frnar.2024.1415530
R. Yamagami, Hina Kubota, Emi Kohno, Hiroyuki Hori
Methyltransferase ribozyme 1 (MTR1) is a catalytic RNA that has been isolated from a random RNA pool by in vitro selection. The ribozyme catalyzes site-specific formation of 1-methyl adenosine (m1A) using 6-methyl guanine (m6G) as a methyl group donor. The ribozyme has been extensively characterized by biochemical and structural analyses. Here, we describe high-throughput screening of single point mutants in the catalytic domain of MTR1 and determine their effect on ribozyme activity. Our mutational profiling method successfully assessed the activity of the 141 MTR1 variants tested in each experiment and revealed that the ribozyme is very sensitive to nucleotide substitutions in the catalytic core domain. Our technique can be applied to methyltransferase ribozymes that catalyze formation of different modifications such as 7-methylguanosine (m7G) or 3-methylcytidine (m3C).
{"title":"High-throughput mutational analysis of a methyltransferase ribozyme","authors":"R. Yamagami, Hina Kubota, Emi Kohno, Hiroyuki Hori","doi":"10.3389/frnar.2024.1415530","DOIUrl":"https://doi.org/10.3389/frnar.2024.1415530","url":null,"abstract":"Methyltransferase ribozyme 1 (MTR1) is a catalytic RNA that has been isolated from a random RNA pool by in vitro selection. The ribozyme catalyzes site-specific formation of 1-methyl adenosine (m1A) using 6-methyl guanine (m6G) as a methyl group donor. The ribozyme has been extensively characterized by biochemical and structural analyses. Here, we describe high-throughput screening of single point mutants in the catalytic domain of MTR1 and determine their effect on ribozyme activity. Our mutational profiling method successfully assessed the activity of the 141 MTR1 variants tested in each experiment and revealed that the ribozyme is very sensitive to nucleotide substitutions in the catalytic core domain. Our technique can be applied to methyltransferase ribozymes that catalyze formation of different modifications such as 7-methylguanosine (m7G) or 3-methylcytidine (m3C).","PeriodicalId":73105,"journal":{"name":"Frontiers in RNA research","volume":"120 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141271868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-03DOI: 10.3389/frnar.2024.1389104
Yunhan Yang, Yanping Li, Rosalie C. Sears, Xiao-Xin Sun, Mushui Dai
Ribosome biogenesis is essential for cell growth, proliferation, and animal development. Its deregulation leads to various human disorders such as ribosomopathies and cancer. Thus, tight regulation of ribosome biogenesis is crucial for normal cell homeostasis. Emerging evidence suggests that posttranslational modifications such as ubiquitination and SUMOylation play a crucial role in regulating ribosome biogenesis. Our recent studies reveal that USP36, a nucleolar deubiquitinating enzyme (DUB), acts also as a SUMO ligase to regulate nucleolar protein group SUMOylation, thereby being essential for ribosome biogenesis. Here, we provide an overview of the current understanding of the SUMOylation regulation of ribosome biogenesis and discuss the role of USP36 in nucleolar SUMOylation.
{"title":"SUMOylation regulation of ribosome biogenesis: Emerging roles for USP36","authors":"Yunhan Yang, Yanping Li, Rosalie C. Sears, Xiao-Xin Sun, Mushui Dai","doi":"10.3389/frnar.2024.1389104","DOIUrl":"https://doi.org/10.3389/frnar.2024.1389104","url":null,"abstract":"Ribosome biogenesis is essential for cell growth, proliferation, and animal development. Its deregulation leads to various human disorders such as ribosomopathies and cancer. Thus, tight regulation of ribosome biogenesis is crucial for normal cell homeostasis. Emerging evidence suggests that posttranslational modifications such as ubiquitination and SUMOylation play a crucial role in regulating ribosome biogenesis. Our recent studies reveal that USP36, a nucleolar deubiquitinating enzyme (DUB), acts also as a SUMO ligase to regulate nucleolar protein group SUMOylation, thereby being essential for ribosome biogenesis. Here, we provide an overview of the current understanding of the SUMOylation regulation of ribosome biogenesis and discuss the role of USP36 in nucleolar SUMOylation.","PeriodicalId":73105,"journal":{"name":"Frontiers in RNA research","volume":"260 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140750204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-20DOI: 10.3389/frnar.2024.1334873
Mónica Padilla-Gálvez, Leo J. Arteaga-Vazquez, Ana B. Villaseñor-Altamirano, Y. Balderas-Martínez, L. Collado-Torres, Javier De Las Rivas, Daniel Blanco-Melo, Alejandra Medina-Rivera
The pathophysiology underlying coronavirus disease 2019 (COVID-19) across tissues and cell types upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains to be fully characterized. Diverse cellular processes have been described, including interferon (IFN) and pro-inflammatory responses and functions of ACE2 and TMPRSS2 proteins. Characterizing how transcriptional programs are activated or repressed could give us a better understanding of the disease progression; this can be better understood via gene regulatory network reverse engineering. Here, we make use of multiple publicly available transcriptional data, such as primary cells and tissue samples obtained from COVID-19 patients’ lung autopsies, to build the transcriptional regulatory networks for each condition. Our results describe the regulatory mechanisms underlying SARS-CoV-2 infection across tissues and cell lines, identifying antiviral and pro-inflammatory networks.
{"title":"Identification of regulons modulating the transcriptional response to SARS-CoV-2 infection in humans","authors":"Mónica Padilla-Gálvez, Leo J. Arteaga-Vazquez, Ana B. Villaseñor-Altamirano, Y. Balderas-Martínez, L. Collado-Torres, Javier De Las Rivas, Daniel Blanco-Melo, Alejandra Medina-Rivera","doi":"10.3389/frnar.2024.1334873","DOIUrl":"https://doi.org/10.3389/frnar.2024.1334873","url":null,"abstract":"The pathophysiology underlying coronavirus disease 2019 (COVID-19) across tissues and cell types upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains to be fully characterized. Diverse cellular processes have been described, including interferon (IFN) and pro-inflammatory responses and functions of ACE2 and TMPRSS2 proteins. Characterizing how transcriptional programs are activated or repressed could give us a better understanding of the disease progression; this can be better understood via gene regulatory network reverse engineering. Here, we make use of multiple publicly available transcriptional data, such as primary cells and tissue samples obtained from COVID-19 patients’ lung autopsies, to build the transcriptional regulatory networks for each condition. Our results describe the regulatory mechanisms underlying SARS-CoV-2 infection across tissues and cell lines, identifying antiviral and pro-inflammatory networks.","PeriodicalId":73105,"journal":{"name":"Frontiers in RNA research","volume":"255 20","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140448526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-19DOI: 10.3389/frnar.2023.1331185
Ryan Johnston, Anne Aldrich, Shawn M. Lyons
Ribosomes are amongst the most ancient molecular machines in cells, showing conservation from the simplest prokaryotes to humans. Ribosomes are an assembly of ribosomal (r)RNA and ribosomal proteins, but the rRNA comprises most of the mass of the ribosome and performs key enzymatic tasks. In humans, rRNA undergoes a laborious maturation that involves multiple processing steps and the deposition of chemical modifications. The correct processing and modification of rRNA ensures the proper function of the mature ribosome. Disturbance of these processes may lead to human disease. Understanding the role of rRNA in protein synthesis and the consequences of its dysregulation is key to deciphering and mitigating the emergence of pathological states in human biology.
{"title":"Roles of ribosomal RNA in health and disease","authors":"Ryan Johnston, Anne Aldrich, Shawn M. Lyons","doi":"10.3389/frnar.2023.1331185","DOIUrl":"https://doi.org/10.3389/frnar.2023.1331185","url":null,"abstract":"Ribosomes are amongst the most ancient molecular machines in cells, showing conservation from the simplest prokaryotes to humans. Ribosomes are an assembly of ribosomal (r)RNA and ribosomal proteins, but the rRNA comprises most of the mass of the ribosome and performs key enzymatic tasks. In humans, rRNA undergoes a laborious maturation that involves multiple processing steps and the deposition of chemical modifications. The correct processing and modification of rRNA ensures the proper function of the mature ribosome. Disturbance of these processes may lead to human disease. Understanding the role of rRNA in protein synthesis and the consequences of its dysregulation is key to deciphering and mitigating the emergence of pathological states in human biology.","PeriodicalId":73105,"journal":{"name":"Frontiers in RNA research","volume":"08 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139612495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-09-17DOI: 10.3389/frnar.2024.1448194
A Gregory Matera, Rebecca E Steiner, C Allie Mills, Benjamin D McMichael, Laura E Herring, Eric L Garcia
Introduction: Molecular chaperones and co-chaperones are highly conserved cellular components that perform a variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an assembly chaperone and serves as a paradigm for studying how specific RNAs are identified and paired with their client substrate proteins to form RNPs. SMN is the eponymous component of a large complex, required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs), that localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN protein forms the oligomeric core of this complex, and missense mutations in the human SMN1 gene are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known. However, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood.
Methods: Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. We carried out affinity purification mass spectrometry (AP-MS) of Drosophila SMN complexes using fly lines exclusively expressing either wildtype or SMA-causing missense alleles.
Results: Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially associated with SMA-causing alleles of SMN.
Discussion: Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.
导言：分子伴侣和共伴侣是高度保守的细胞成分，它们履行着与蛋白质组的正确三维折叠有关的各种职责。执行这一重要任务的因子网络被称为蛋白稳定网络（PN）。就核糖核蛋白（RNPs）与蛋白停滞网络的联系而言，RNPs 是一个尚未充分开发的领域。生存运动神经元（Survival Motor Neuron，SMN）复合体是一种组装伴侣，是研究特定 RNA 如何被识别并与其客户底物蛋白配对以形成 RNPs 的范例。SMN是一个大型复合体的同名成分，富含尿苷的小型核核糖核蛋白（U-snRNPs）的生物生成需要它，该复合体定位在动物细胞核和细胞质中不同的无膜细胞器上。SMN 蛋白是这一复合体的寡聚核心，人类 SMN1 基因的错义突变可导致脊髓性肌肉萎缩症（SMA）。了解 snRNA 如何组装成 U-snRNPs 的基本框架是已知的。然而，人们对细胞用于调节其生物发生的途径和机制却知之甚少：鉴于这些过程对正常发育和神经退行性疾病的重要性，我们着手鉴定和描述新型 SMN 结合伙伴。我们利用专门表达野生型或导致 SMA 的错义等位基因的蝇系，对果蝇 SMN 复合物进行了亲和纯化质谱分析（AP-MS）：对下拉式数据进行的生物信息学分析，以及与在人类细胞中进行的接近标记研究的比较，揭示了与至少两个其他主要伴侣蛋白系统的保守联系，包括热休克折叠伴侣蛋白（HSPs）和组蛋白/核小体组装伴侣蛋白。值得注意的是，我们发现热休克同源蛋白 Hsc70-4 和其他 HspA 家族成员优先与 SMN 的 SMA 致病等位基因相关：Hsc70-4特别有趣，因为在小鼠和果蝇ALS（肌萎缩性脊髓侧索硬化症）疾病模型中，它的mRNA被突变形式的TDP-43异常封闭。最重要的是，Hsc70-4（哺乳动物中的 HspA8）的错义等位基因最近被确定为小鼠 SMA 表型的旁路抑制因子。这些发现共同表明，与伴侣相关的功能障碍是 ALS 和 SMA 的病因根源。
{"title":"Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.","authors":"A Gregory Matera, Rebecca E Steiner, C Allie Mills, Benjamin D McMichael, Laura E Herring, Eric L Garcia","doi":"10.3389/frnar.2024.1448194","DOIUrl":"10.3389/frnar.2024.1448194","url":null,"abstract":"<p><strong>Introduction: </strong>Molecular chaperones and co-chaperones are highly conserved cellular components that perform a variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an assembly chaperone and serves as a paradigm for studying how specific RNAs are identified and paired with their client substrate proteins to form RNPs. SMN is the eponymous component of a large complex, required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs), that localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN protein forms the oligomeric core of this complex, and missense mutations in the human <i>SMN1</i> gene are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known. However, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood.</p><p><strong>Methods: </strong>Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. We carried out affinity purification mass spectrometry (AP-MS) of <i>Drosophila</i> SMN complexes using fly lines exclusively expressing either wildtype or SMA-causing missense alleles.</p><p><strong>Results: </strong>Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially associated with SMA-causing alleles of SMN.</p><p><strong>Discussion: </strong>Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and <i>Drosophila</i> ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.</p>","PeriodicalId":73105,"journal":{"name":"Frontiers in RNA research","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-06DOI: 10.3389/frnar.2023.1248236
Nicole Simms, John R. P. Knight
Unlike DNA, RNA can be found in every sub-cellular compartment, where it is used to impart the genetic code or perform essential catalytic activities. As a result, damage to RNA is more spatially pervasive than damage to DNA and can have profound effects on gene expression and RNA-dependent activities. The past decade has seen the pathways involved in detecting and responding to damage of specific RNAs defined. These studies largely used high concentrations of tool compounds or deletion of essential factors for the response to RNA damage to study its effects. RNA is damaged by both endogenous and exogenous agents, with the effect of exogenous agents administered as therapeutics the focus of this review. In an effort to formalise studies into clinical RNA damage biology we propose 4 types of RNA damaging drug that we divide into 2 broad classes. Class 1 drugs result from synthesis using non-canonical nucleotides, which are incorporated into RNA in place of the canonical nucleotides. This class is subdivided depending on the outcome of this misincorporation on the nascent transcript. Class 2 drugs result in covalent ligation of moieties that alter RNA structure. This class is subdivided according to the functionality of the covalent ligation—class 2a are monovalent while class 2b are divalent. We discuss the evidence for and mechanisms of RNA damage as well as highlighting the unknown factors that require further investigation to determine the molecular mechanisms of these drugs.
{"title":"RNA damage: the forgotten target of clinical compounds","authors":"Nicole Simms, John R. P. Knight","doi":"10.3389/frnar.2023.1248236","DOIUrl":"https://doi.org/10.3389/frnar.2023.1248236","url":null,"abstract":"Unlike DNA, RNA can be found in every sub-cellular compartment, where it is used to impart the genetic code or perform essential catalytic activities. As a result, damage to RNA is more spatially pervasive than damage to DNA and can have profound effects on gene expression and RNA-dependent activities. The past decade has seen the pathways involved in detecting and responding to damage of specific RNAs defined. These studies largely used high concentrations of tool compounds or deletion of essential factors for the response to RNA damage to study its effects. RNA is damaged by both endogenous and exogenous agents, with the effect of exogenous agents administered as therapeutics the focus of this review. In an effort to formalise studies into clinical RNA damage biology we propose 4 types of RNA damaging drug that we divide into 2 broad classes. Class 1 drugs result from synthesis using non-canonical nucleotides, which are incorporated into RNA in place of the canonical nucleotides. This class is subdivided depending on the outcome of this misincorporation on the nascent transcript. Class 2 drugs result in covalent ligation of moieties that alter RNA structure. This class is subdivided according to the functionality of the covalent ligation—class 2a are monovalent while class 2b are divalent. We discuss the evidence for and mechanisms of RNA damage as well as highlighting the unknown factors that require further investigation to determine the molecular mechanisms of these drugs.","PeriodicalId":73105,"journal":{"name":"Frontiers in RNA research","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77942769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-14DOI: 10.3389/frnar.2023.1240635
Eleanna Kazana, Tobias von der Haar
Introduction: In addition to the widespread and well documented control of protein synthesis by translation initiation, recent evidence suggests that translation elongation can also control protein synthesis rates. One of the proposed mechanisms leading to elongation control is the interference of slow ribosome movement around the start codon with efficient translation initiation. Here we estimate the frequency with which this mode of control occurs in baker’s yeast growing in rich medium. Methods: We interrogate published genome-wide datasets for evidence of transcripts associated with queueing small ribosomal subunits, and confirm results from these surveys using additional experimental work. Results: Our analyses reveal that transcripts from around 20% of yeast genes show evidence of queueing ribosomes, which may be indicative of translation elongation control. Moreover, this subset of transcripts is sensitive to distinct regulatory signals compared to initiation-controlled mRNAs, and such distinct regulation occurs, for example, during the response to osmotic stress. Discussion: Our analyses provide a first quantitative estimate for the prevalence of translational control exerted via the elongation stage in a commonly used model organism, and suggest that transcript under elongation control form a separately addressable RNA regulon.
{"title":"On translational control by ribosome speed in S. cerevisiae","authors":"Eleanna Kazana, Tobias von der Haar","doi":"10.3389/frnar.2023.1240635","DOIUrl":"https://doi.org/10.3389/frnar.2023.1240635","url":null,"abstract":"Introduction: In addition to the widespread and well documented control of protein synthesis by translation initiation, recent evidence suggests that translation elongation can also control protein synthesis rates. One of the proposed mechanisms leading to elongation control is the interference of slow ribosome movement around the start codon with efficient translation initiation. Here we estimate the frequency with which this mode of control occurs in baker’s yeast growing in rich medium. Methods: We interrogate published genome-wide datasets for evidence of transcripts associated with queueing small ribosomal subunits, and confirm results from these surveys using additional experimental work. Results: Our analyses reveal that transcripts from around 20% of yeast genes show evidence of queueing ribosomes, which may be indicative of translation elongation control. Moreover, this subset of transcripts is sensitive to distinct regulatory signals compared to initiation-controlled mRNAs, and such distinct regulation occurs, for example, during the response to osmotic stress. Discussion: Our analyses provide a first quantitative estimate for the prevalence of translational control exerted via the elongation stage in a commonly used model organism, and suggest that transcript under elongation control form a separately addressable RNA regulon.","PeriodicalId":73105,"journal":{"name":"Frontiers in RNA research","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135264361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-10DOI: 10.3389/frnar.2023.1226610
P. Adjibade, R. Mazroui
Stress granules (SG) are macro-complexes that assemble as phase-separated and dynamic RNA biocondensates in the cytoplasm of the eukaryotic cell when the initiation step of the general translation of mRNAs is stalled. This occurs mainly as an adaptive cell response to either environmental (i.e., radiation, exposure to chemical drugs), pathological (i.e., viral treatment), physiological (i.e., oxygen-, amino acids-, and glucose-deprivation), or therapeutic (i.e., treatment with anti-cancer drugs) translational stress. SG also formed when translation initiation is blocked through stress-independent events including alteration of the activities of specific translation initiation factors and RNA-binding proteins. Both stress-dependent and–independent inhibition of translation initiation results in the accumulation of untranslated mRNAs, considered as integral components of SG. Consistently, in vivo assays of SG assembly combined with in vitro-based assembly of SG-like biocondensates studies support a fundamental role of the accumulation of untranslated mRNA in initiating the formation of SG, which then further promote their repression, potentially in a feed-back regulatory mechanism. The potential role of SG in actively repressing translation of associated mRNAs has been supported by a number of functional studies, establishing SG as critical regulatory sites of RNA homeostasis, in particular during stress. The view that the SG environment restricts translation of associated mRNAs was however challenged in studies showing that stress-induced translation repression can occur similarly in absence and presence of SG, leading to the emerging concept that formation of SG and translation repression are uncoupled processes. While it still a debate if mRNA recruitment to SG contributes to their translation repression, recent finding reported translation of reporter mRNAs in SG, suggesting rather an active translational role of SG. In this review, we describe the main translational signaling pathways that regulate the biology of SG, summarize current data supporting RNA as an integral functional component of SG, and then discuss evidence supporting or not the role of SG in regulating translation either negatively or positively during stress.
{"title":"Stress granules: stress-induced cytoplasmic mRNPs compartments linked to mRNA translational regulatory pathways","authors":"P. Adjibade, R. Mazroui","doi":"10.3389/frnar.2023.1226610","DOIUrl":"https://doi.org/10.3389/frnar.2023.1226610","url":null,"abstract":"Stress granules (SG) are macro-complexes that assemble as phase-separated and dynamic RNA biocondensates in the cytoplasm of the eukaryotic cell when the initiation step of the general translation of mRNAs is stalled. This occurs mainly as an adaptive cell response to either environmental (i.e., radiation, exposure to chemical drugs), pathological (i.e., viral treatment), physiological (i.e., oxygen-, amino acids-, and glucose-deprivation), or therapeutic (i.e., treatment with anti-cancer drugs) translational stress. SG also formed when translation initiation is blocked through stress-independent events including alteration of the activities of specific translation initiation factors and RNA-binding proteins. Both stress-dependent and–independent inhibition of translation initiation results in the accumulation of untranslated mRNAs, considered as integral components of SG. Consistently, in vivo assays of SG assembly combined with in vitro-based assembly of SG-like biocondensates studies support a fundamental role of the accumulation of untranslated mRNA in initiating the formation of SG, which then further promote their repression, potentially in a feed-back regulatory mechanism. The potential role of SG in actively repressing translation of associated mRNAs has been supported by a number of functional studies, establishing SG as critical regulatory sites of RNA homeostasis, in particular during stress. The view that the SG environment restricts translation of associated mRNAs was however challenged in studies showing that stress-induced translation repression can occur similarly in absence and presence of SG, leading to the emerging concept that formation of SG and translation repression are uncoupled processes. While it still a debate if mRNA recruitment to SG contributes to their translation repression, recent finding reported translation of reporter mRNAs in SG, suggesting rather an active translational role of SG. In this review, we describe the main translational signaling pathways that regulate the biology of SG, summarize current data supporting RNA as an integral functional component of SG, and then discuss evidence supporting or not the role of SG in regulating translation either negatively or positively during stress.","PeriodicalId":73105,"journal":{"name":"Frontiers in RNA research","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72895840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-10DOI: 10.3389/frnar.2023.1257775
Rei Yoshimoto, Shinichi Nakagawa
Short Interspersed Elements (SINEs) comprise a significant portion of the genomes of higher eukaryotes, including humans and mice. This review focuses on SINE-derived noncoding RNAs (ncRNAs), particularly BC1, BC200, and 4.5SH RNA, which are expressed abundantly and in a species-specific manner. These ncRNAs seem to have independently evolved their functions during evolutionary processes: BC1 and BC200 have become cytoplasmic translation inhibitors, while 4.5SH RNA has developed into a nuclear ncRNA that regulates splicing. This review delves into the unique roles of these ncRNAs, with a special emphasis on the recently discovered splicing regulation function of 4.5SH RNA. Furthermore, we discuss their evolutionary trajectories and potential implications for understanding the complexities of gene regulation.
{"title":"SINE-derived short noncoding RNAs: their evolutionary origins, molecular mechanisms, and physiological significance","authors":"Rei Yoshimoto, Shinichi Nakagawa","doi":"10.3389/frnar.2023.1257775","DOIUrl":"https://doi.org/10.3389/frnar.2023.1257775","url":null,"abstract":"Short Interspersed Elements (SINEs) comprise a significant portion of the genomes of higher eukaryotes, including humans and mice. This review focuses on SINE-derived noncoding RNAs (ncRNAs), particularly BC1, BC200, and 4.5SH RNA, which are expressed abundantly and in a species-specific manner. These ncRNAs seem to have independently evolved their functions during evolutionary processes: BC1 and BC200 have become cytoplasmic translation inhibitors, while 4.5SH RNA has developed into a nuclear ncRNA that regulates splicing. This review delves into the unique roles of these ncRNAs, with a special emphasis on the recently discovered splicing regulation function of 4.5SH RNA. Furthermore, we discuss their evolutionary trajectories and potential implications for understanding the complexities of gene regulation.","PeriodicalId":73105,"journal":{"name":"Frontiers in RNA research","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88770711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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