Special Issue "RNA Editing"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 October 2016).

Special Issue Editor

Prof. Dr. H. Ulrich Göringer
E-Mail Website
Guest Editor
Department of Molecular Genetics, Darmstadt University of Technology, 64287 Darmstadt, Germany
Interests: RNA editing; post-transcriptional gene regulation; RNA-structure/function; RNA-folding; RNA/protein interaction; RNA-aptamers; gene regulation in protozoan parasites; RNA-thermometers

Special Issue Information

Dear Colleagues,

This year marks the 30th anniversary of the first observation of an RNA editing phenomenon. In their seminal paper in 1986 Rob Benne and colleagues (Cell 46, 819–826) identified four reading-frame restoring U-nucleotides in the cytochrome oxidase subunit II (COII) mRNA of the protozoan organisms Trypanosoma brucei and Crithidia fasciculata. The observation led to the conclusion: “… that the extra nucleotides are added during or after transcription… by an RNA-editing process”. This very sentence marks the inception of all RNA-editing phenomena known to us today and the iconoclastic ”beauty” of the process in contradicting the “central dogma” still emanates from these few words. Thirty years later, one is astounded as to the many facets of RNA-editing in nearly all organisms and in a great number of biochemical and cellular pathways. Although the different reactions rely on different enzymes and macromolecular machineries, many conceptual and mechanistic crossover points exist, which have proven instrumental in advancing all RNA editing subdisciplines. In a single issue of Genes in 2017, we would like to summarize the current state of understanding of RNA-editing by showcasing the entire spectrum of ongoing research in the field. We welcome original articles as well as reviews of all types of RNA editing in all systems with a special emphasis on new perspectives and interpretations as well as novel technological and theoretical advances.

Prof. Dr. H. Ulrich Göringer
Guest Editor

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Published Papers (9 papers)

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Research

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Open AccessArticle
A Comparative Study of the Structural Dynamics of Four Terminal Uridylyl Transferases
Genes 2017, 8(6), 166; https://doi.org/10.3390/genes8060166 - 20 Jun 2017
Viewed by 1601
Abstract
African trypanosomiasis occurs in 36 countries in sub-Saharan Africa with 10,000 reported cases annually. No definitive remedy is currently available and if left untreated, the disease becomes fatal. Structural and biochemical studies of trypanosomal terminal uridylyl transferases (TUTases) demonstrated their functional role in [...] Read more.
African trypanosomiasis occurs in 36 countries in sub-Saharan Africa with 10,000 reported cases annually. No definitive remedy is currently available and if left untreated, the disease becomes fatal. Structural and biochemical studies of trypanosomal terminal uridylyl transferases (TUTases) demonstrated their functional role in extensive uridylate insertion/deletion of RNA. Trypanosoma brucei RNA Editing TUTase 1 (TbRET1) is involved in guide RNA 3’ end uridylation and maturation, while TbRET2 is responsible for U-insertion at RNA editing sites. Two additional TUTases called TbMEAT1 and TbTUT4 have also been reported to share similar function. TbRET1 and TbRET2 are essential enzymes for the parasite viability making them potential drug targets. For this study, we clustered molecular dynamics (MD) trajectories of four TUTases based on active site shape measured by Pocket Volume Measurer (POVME) program. Among the four TUTases, TbRET1 exhibited the largest average pocket volume, while TbMEAT1’s and TbTUT4’s active sites displayed the most flexibility. A side pocket was also identified within the active site in all TUTases with TbRET1 having the most pronounced. Our results indicate that TbRET1’s larger side pocket can be exploited to achieve selective inhibitor design as FTMap identifies it as a druggable pocket. Full article
(This article belongs to the Special Issue RNA Editing)
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Open AccessArticle
Differential Binding of Three Major Human ADAR Isoforms to Coding and Long Non-Coding Transcripts
Genes 2017, 8(2), 68; https://doi.org/10.3390/genes8020068 - 11 Feb 2017
Cited by 19 | Viewed by 3993
Abstract
RNA editing by deamination of adenosine to inosine is an evolutionarily conserved process involved in many cellular pathways, from alternative splicing to miRNA targeting. In humans, it is carried out by no less than three major adenosine deaminases acting on RNA (ADARs): ADAR1-p150, [...] Read more.
RNA editing by deamination of adenosine to inosine is an evolutionarily conserved process involved in many cellular pathways, from alternative splicing to miRNA targeting. In humans, it is carried out by no less than three major adenosine deaminases acting on RNA (ADARs): ADAR1-p150, ADAR1-p110, and ADAR2. However, the first two derive from alternative splicing, so that it is currently impossible to delete ADAR1-p110 without also knocking out ADAR1-p150 expression. Furthermore, the expression levels of ADARs varies wildly among cell types, and no study has systematically explored the effect of each of these isoforms on the cell transcriptome. In this study, RNA immunoprecipitation (RIP)-sequencing on overexpressed ADAR isoforms tagged with green fluorescent protein (GFP) shows that each ADAR is associated with a specific set of differentially expressed genes, and that they each bind to distinct set of RNA targets. Our results show a good overlap with known edited transcripts, establishing RIP-seq as a valid method for the investigation of RNA editing biology. Full article
(This article belongs to the Special Issue RNA Editing)
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Open AccessArticle
Applying Human ADAR1p110 and ADAR1p150 for Site-Directed RNA Editing—G/C Substitution Stabilizes GuideRNAs against Editing
Genes 2017, 8(1), 34; https://doi.org/10.3390/genes8010034 - 14 Jan 2017
Cited by 12 | Viewed by 2874
Abstract
Site-directed RNA editing is an approach to reprogram genetic information at the RNA level. We recently introduced a novel guideRNA that allows for the recruitment of human ADAR2 to manipulate genetic information. Here, we show that the current guideRNA design is already able [...] Read more.
Site-directed RNA editing is an approach to reprogram genetic information at the RNA level. We recently introduced a novel guideRNA that allows for the recruitment of human ADAR2 to manipulate genetic information. Here, we show that the current guideRNA design is already able to recruit another human deaminase, ADAR1, in both isoforms, p110 and p150. However, further optimization seems necessary as the current design is less efficient for ADAR1 isoforms. Furthermore, we describe hotspots at which the guideRNA itself is edited and show a way to circumvent this auto-editing without losing editing efficiency at the target. Both findings are important for the advancement of site-directed RNA editing as a tool in basic biology or as a platform for therapeutic editing. Full article
(This article belongs to the Special Issue RNA Editing)
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Open AccessArticle
Identification and Analysis of RNA Editing Sites in the Chloroplast Transcripts of Aegilops tauschii L.
Genes 2017, 8(1), 13; https://doi.org/10.3390/genes8010013 - 30 Dec 2016
Cited by 16 | Viewed by 2624
Abstract
RNA editing is an important way to convert cytidine (C) to uridine (U) at specific sites within RNA molecules at a post-transcriptional level in the chloroplasts of higher plants. Although it has been systematically studied in many plants, little is known about RNA [...] Read more.
RNA editing is an important way to convert cytidine (C) to uridine (U) at specific sites within RNA molecules at a post-transcriptional level in the chloroplasts of higher plants. Although it has been systematically studied in many plants, little is known about RNA editing in the wheat D genome donor Aegilops tauschii L. Here, we investigated the chloroplast RNA editing of Ae. tauschii and compared it with other wheat relatives to trace the evolution of wheat. Through bioinformatics prediction, a total of 34 C-to-U editing sites were identified, 17 of which were validated using RT-PCR product sequencing. Furthermore, 60 sites were found by the RNA-Seq read mapping approach, 24 of which agreed with the prediction and six were validated experimentally. The editing sites were biased toward tCn or nCa trinucleotides and 5′-pyrimidines, which were consistent with the flanking bases of editing sites of other seed plants. Furthermore, the editing events could result in the alteration of the secondary structures and topologies of the corresponding proteins, suggesting that RNA editing might impact the function of target genes. Finally, comparative analysis found some evolutionarily conserved editing sites in wheat and two species-specific sites were also obtained. This study is the first to report on RNA editing in Aegilops tauschii L, which not only sheds light on the evolution of wheat from the point of view of RNA editing, but also lays a foundation for further studies to identify the mechanisms of C-to-U alterations. Full article
(This article belongs to the Special Issue RNA Editing)
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Open AccessArticle
Electroporation of DNA into Physarum polycephalum Mitochondria: Effects on Transcription and RNA Editing in Isolated Organelles
Genes 2016, 7(12), 128; https://doi.org/10.3390/genes7120128 - 14 Dec 2016
Cited by 2 | Viewed by 2343
Abstract
Mitochondrial RNAs in the acellular slime mold Physarum polycephalum contain nucleotides that are not encoded in the mitochondrial genes from which they are transcribed. These site-specific changes are quite extensive, comprising ~4% of the residues within mRNAs and ~2% of rRNAs and tRNAs. [...] Read more.
Mitochondrial RNAs in the acellular slime mold Physarum polycephalum contain nucleotides that are not encoded in the mitochondrial genes from which they are transcribed. These site-specific changes are quite extensive, comprising ~4% of the residues within mRNAs and ~2% of rRNAs and tRNAs. These “extra” nucleotides are added co-transcriptionally, but the means by which this is accomplished have not been elucidated. The cox1 mRNA also contains four sites of C to U changes, which occur post-transcriptionally, most likely via targeted deamination. The currently available in vitro systems for studying P. polycephalum editing are limited in that the template is the entire ~63,000 bp mitochondrial genome. This presents a significant challenge when trying to define the signals that specify editing sites. In an attempt to overcome this issue, a method for introducing DNA into isolated P. polycephalum mitochondria via electroporation has been developed. Exogenous DNA is expressed, but the transcripts synthesized from these templates are not edited under the conditions tested. However, transcripts derived from the mitochondrial genome are accurately edited after electroporation, indicating that the editing machinery is still functional. These findings suggest that this method may ultimately provide a feasible approach to elucidating editing signals. Full article
(This article belongs to the Special Issue RNA Editing)
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Review

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Open AccessReview
Altered Intracellular Milieu of ADAR2-Deficient Motor Neurons in Amyotrophic Lateral Sclerosis
Genes 2017, 8(2), 60; https://doi.org/10.3390/genes8020060 - 08 Feb 2017
Cited by 9 | Viewed by 3349
Abstract
Transactive response DNA-binding protein (TDP-43) pathology, and failure of A-to-I conversion (RNA editing) at the glutamine/arginine (Q/R) site of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of most patients with amyotrophic lateral [...] Read more.
Transactive response DNA-binding protein (TDP-43) pathology, and failure of A-to-I conversion (RNA editing) at the glutamine/arginine (Q/R) site of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of most patients with amyotrophic lateral sclerosis (ALS). Adenosine deaminase acting on RNA 2 (ADAR2) specifically catalyzes GluA2 Q/R site-RNA editing. Furthermore, conditional ADAR2 knockout mice (AR2) exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons, which is the most reliable pathological marker of ALS. Therefore, the evidence indicates that ADAR2 downregulation is a causative factor in ALS, and AR2 mice exhibit causative molecular changes that occur in ALS. We discuss the contributors to ADAR2 downregulation and TDP-43 pathology in AR2 mouse motor neurons. We describe mechanisms of exaggerated Ca2+ influx amelioration via AMPA receptors, which is neuroprotective in ADAR2-deficient motor neurons with normalization of TDP-43 pathology in AR2 mice. Development of drugs to treat diseases requires appropriate animal models and a sensitive method of evaluating efficacy. Therefore, normalization of disrupted intracellular environments resulting from ADAR2 downregulation may be a therapeutic target for ALS. We discuss the development of targeted therapy for ALS using the AR2 mouse model. Full article
(This article belongs to the Special Issue RNA Editing)
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Open AccessReview
RNA Editing, ADAR1, and the Innate Immune Response
Genes 2017, 8(1), 41; https://doi.org/10.3390/genes8010041 - 18 Jan 2017
Cited by 14 | Viewed by 4253
Abstract
RNA editing, particularly A-to-I RNA editing, has been shown to play an essential role in mammalian embryonic development and tissue homeostasis, and is implicated in the pathogenesis of many diseases including skin pigmentation disorder, autoimmune and inflammatory tissue injury, neuron degeneration, and various [...] Read more.
RNA editing, particularly A-to-I RNA editing, has been shown to play an essential role in mammalian embryonic development and tissue homeostasis, and is implicated in the pathogenesis of many diseases including skin pigmentation disorder, autoimmune and inflammatory tissue injury, neuron degeneration, and various malignancies. A-to-I RNA editing is carried out by a small group of enzymes, the adenosine deaminase acting on RNAs (ADARs). Only three members of this protein family, ADAR1–3, exist in mammalian cells. ADAR3 is a catalytically null enzyme and the most significant function of ADAR2 was found to be in editing on the neuron receptor GluR-B mRNA. ADAR1, however, has been shown to play more significant roles in biological and pathological conditions. Although there remains much that is not known about how ADAR1 regulates cellular function, recent findings point to regulation of the innate immune response as an important function of ADAR1. Without appropriate RNA editing by ADAR1, endogenous RNA transcripts stimulate cytosolic RNA sensing receptors and therefore activate the IFN-inducing signaling pathways. Overactivation of innate immune pathways can lead to tissue injury and dysfunction. However, obvious gaps in our knowledge persist as to how ADAR1 regulates innate immune responses through RNA editing. Here, we review critical findings from ADAR1 mechanistic studies focusing on its regulatory function in innate immune responses and identify some of the important unanswered questions in the field. Full article
(This article belongs to the Special Issue RNA Editing)
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Open AccessReview
RNA Editing and Its Molecular Mechanism in Plant Organelles
Genes 2017, 8(1), 5; https://doi.org/10.3390/genes8010005 - 23 Dec 2016
Cited by 73 | Viewed by 4806
Abstract
RNA editing by cytidine (C) to uridine (U) conversions is widespread in plant mitochondria and chloroplasts. In some plant taxa, “reverse” U-to-C editing also occurs. However, to date, no instance of RNA editing has yet been reported in green algae and the complex [...] Read more.
RNA editing by cytidine (C) to uridine (U) conversions is widespread in plant mitochondria and chloroplasts. In some plant taxa, “reverse” U-to-C editing also occurs. However, to date, no instance of RNA editing has yet been reported in green algae and the complex thalloid liverworts. RNA editing may have evolved in early land plants 450 million years ago. However, in some plant species, including the liverwort, Marchantia polymorpha, editing may have been lost during evolution. Most RNA editing events can restore the evolutionarily conserved amino acid residues in mRNAs or create translation start and stop codons. Therefore, RNA editing is an essential process to maintain genetic information at the RNA level. Individual RNA editing sites are recognized by plant-specific pentatricopeptide repeat (PPR) proteins that are encoded in the nuclear genome. These PPR proteins are characterized by repeat elements that bind specifically to RNA sequences upstream of target editing sites. In flowering plants, non-PPR proteins also participate in multiple RNA editing events as auxiliary factors. C-to-U editing can be explained by cytidine deamination. The proteins discovered to date are important factors for RNA editing but a bona fide RNA editing enzyme has yet to be identified. Full article
(This article belongs to the Special Issue RNA Editing)
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Open AccessReview
Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases
Genes 2016, 7(12), 129; https://doi.org/10.3390/genes7120129 - 17 Dec 2016
Cited by 36 | Viewed by 3996
Abstract
Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA (dsRNA). Among the three types of mammalian ADARs, ADAR1 has long been recognized as an essential enzyme for normal development. The interferon-inducible ADAR1p150 is involved in immune responses to both [...] Read more.
Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA (dsRNA). Among the three types of mammalian ADARs, ADAR1 has long been recognized as an essential enzyme for normal development. The interferon-inducible ADAR1p150 is involved in immune responses to both exogenous and endogenous triggers, whereas the functions of the constitutively expressed ADAR1p110 are variable. Recent findings that ADAR1 is involved in the recognition of self versus non-self dsRNA provide potential explanations for its links to hematopoiesis, type I interferonopathies, and viral infections. Editing in both coding and noncoding sequences results in diseases ranging from cancers to neurological abnormalities. Furthermore, editing of noncoding sequences, like microRNAs, can regulate protein expression, while editing of Alu sequences can affect translational efficiency and editing of proximal sequences. Novel identifications of long noncoding RNA and retrotransposons as editing targets further expand the effects of A-to-I editing. Besides editing, ADAR1 also interacts with other dsRNA-binding proteins in editing-independent manners. Elucidating the disease-specific patterns of editing and/or ADAR1 expression may be useful in making diagnoses and prognoses. In this review, we relate the mechanisms of ADAR1′s actions to its pathological implications, and suggest possible mechanisms for the unexplained associations between ADAR1 and human diseases. Full article
(This article belongs to the Special Issue RNA Editing)
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