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PubMed1994

RNA editing of tRNA(Phe) and tRNA(Cys) in mitochondria of Oenothera berteriana is initiated in precursor molecules.

We have analyzed the role of RNA editing in the correction of mismatched base pairs in tRNA secondary structures in mitochondria of the flowering plant Oenothera berteriana. Comparison of genomic and cDNA sequences from unprocessed primary transcripts of the newly characterized genes for tRNA(Cys), tRNA(Asn) and tRNA(Ile) and the previously described gene for tRNA(Phe) revealed single nucleotide discrepancies in the tRNA(Cys) and tRNA(Phe) sequences. While the change in the anticodon stem of tRNA(Cys) alters a C-T to a T-T mismatch, the nucleotide transition in the tRNA(Phe) restores a conventional T-A Watson-Crick base pair, replacing a C-A mismatch in the acceptor stem. Since both nucleotide alterations are conversions from genomic cytidines to thymidines in the cDNA (uridines in the tRNAs), they are attributed to RNA editing, which is observed in nearly all mRNAs from plant mitochondria.

Base Sequence↗
PubMed2002

Transcript mutations of the alpha regulatory subunit of protein kinase A and up-regulation of the RNA-editing gene transcript in lupus T lymphocytes.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterised by diverse dysfunctions of immune effector cells, including proliferation and cytotoxicity. In T cells from patients with SLE, activity of type 1 protein kinase A isozymes is greatly reduced because of decreased expression of the alpha and beta regulatory subunits (RI alpha and RI beta). We aimed to identify a molecular mechanism or mechanisms for this isozyme deficiency by assessing occurrence of mutations in transcripts of the RI alpha subunit in patients with SLE. METHODS: We cloned and sequenced cDNA of RI alpha and corresponding genomic DNA of the coding region to detect sequence changes from eight patients with SLE and six healthy controls. Because transcript editing is regulated by adenosine deaminases that act on RNA (ADAR), we quantified expression of ADAR1 transcripts in SLE and control T cells by competitive PCR. FINDINGS: Sequence analyses of cDNA showed heterogeneous transcript mutations, including deletions, transitions, and transversions. We identified 1.22 x 10(-3)/bp transcript mutations in SLE T cells-a frequency 7.5 times higher than that in control T cells. By contrast, we identified no genomic mutations. Two hotspots were identified in the RI alpha subunit transcripts from SLE T cells, one located adjacent to a pseudosubstrate site of the RI alpha subunit and the other a component of the cAMP binding A domain. ADAR1 mRNA content was 3.5 times higher in SLE cells than in control T cells (p=0.001). INTERPRETATION: An RNA-editing enzyme could be converting adenosine to inosine within double-stranded regions of RNA, resulting in transcript mutations. This process could be one mechanism resulting in mutations in the RI alpha subunit of type 1 protein kinase A.

Adenosine Deaminase↗
PubMed2006

Molecular pathopharmacology of 5-HT2C receptors and the RNA editing in the brain.

Among the 14 kinds of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes (5-HTR), 5-HT(2C) receptor (5-HT2CR) has been intensively investigated because of its physiologically and pathophysiologically important role in the brain. 5-HT2CR has been suggested to be involved in depressive disorders based on findings from pharmacological/neurochemical/behavioral studies using autopsy preparations of humans suffering from depression, animal models of depression, and animals treated with antidepressant drugs. Recently the editing of 5-HT2CR mRNA has been reported to participate in the pathogenesis of depressive disease. The RNA editing of 5-HT2CR induced by the presumable alteration of deaminase during a pathological state in depression causes changes of a base to another base (e.g., adenosine to guanosine, cytidine to uracil (thymidine)), followed by changes in amino acids constituting the second intracellular transmembrane loop that couples G proteins. Thus 5-HT2CR receptor-mediated signal transduction is changed. In the present review, the pathopharmacological significance of 5-HT2CR in special reference to RNA editing of receptors is reviewed and discussed from the aspect of development of novel therapeutics for depression.

Adenosine Deaminase↗
PubMed1998

RNA editing in the Drosophila DMCA1A calcium-channel alpha 1 subunit transcript.

Messenger RNA editing of transcripts encoding voltage-sensitive ion channels has not been extensively analyzed--least of all in Drosophila, for which several channel-encoding genes are known. Previous sequence studies of D. melanogaster's cacophony gene, which encodes an alpha 1 calcium-channel subunit called Dmca1A, suggested that several nucleotides within the ORF of the primary transcript are edited such that "A-to-G" substitutions occur (these two nucleotides being the adenine that is found at the relevant sites in the sense strand of genomic DNA or the primary transcript, compared to the substitution of guanine that is detected at the level of cDNA analysis). Such A-to-G changes are the same kind of post-transcriptional variations originally discovered--in a neurobiological context--for a ligand-sensitive channel in vertebrates. Here, we extracted RNA from adult flies and revealed, by RT-PCR and restriction-enzyme analyses, that transcript heterogeneity exists in vivo for three distinct edited sites within the cac-encoded RNA. Each such nucleotide would lead to channel variability at the level of the Dmca1A polypeptide. Owing to cacophony being originally identified as a "behavioral gene," the possible significance of Dmca1A RNA editing for influencing the relevant neuro-functional phenotypes is discussed.

Animals↗
PubMed1998

RNA editing: trypanosomes rewrite the genetic code.

The understanding of how genetic information is stored and expressed has advanced considerably since the "central dogma" asserted that genetic information flows from the nucleotide sequence of DNA to that of messenger RNA (mRNA) which in turn specifies the amino acid sequence of a protein. It was found that genetic information can be stored as RNA (e.g. in RNA viruses) and can flow from RNA to DNA by reverse transcriptase enzyme activity. In addition, some genes contain introns, nucleotide sequences that are removed from their RNA (by RNA splicing) and thus are not represented in the resultant protein. Furthermore, alternative splicing was found to produce variant proteins from a single gene. More recently, the study of trypanosome parasites revealed an unexpected and indeed counter-intuitive genetic complexity. Genetic information for a single protein can be dispersed among several (DNA) genes in these organisms. One of these genes specifies an encrypted precursor mRNA that is converted to a functional mRNA by a process called RNA editing that inserts and deletes uridylate nucleotides. The sequence of the edited mRNA is specified by multiple small RNAs, named guide RNAs, (gRNAs) each of which is encoded in a separate gene. Thus, edited mRNA sequences are assembled from multiple genes by the transfer of information from one type of RNA to another. The existence of editing was surprising but has stimulated the discovery of other types of RNA editing. The Stuart laboratory has been exploring RNA editing in trypanosomes from the time of its discovery. They found dramatic differences between the mitochondrial gene sequences and those of the corresponding mRNAs, which indicated editing by the insertion and deletion of uridylates. Some editing was modest; simply eliminating shifts in sequence register of minimally extending the protein coding sequence. However, editing of many mRNAs was startingly extensive. The RNA sequence was essentially entirely remodeled with its sequence more the result of editing than the gene sequence. The identities of genes for such extensively edited RNA were not recognizable from the DNA sequence but they were readily identifiable from the edited mRNA sequence. Thus, despite the complex and extensive editing the resultant mRNA sequence is precise. Characterization of partially edited RNAs indicated that editing proceeds in the direction opposite to that used to specify the protein which reflects the use of the gRNAs. The numerous gRNAs that are used for editing are encoded in the DNA molecules whose role was previously a mystery. Using information gained in our earlier studies, the Stuart group developed an in vitro system that reproduces the fundamental process of editing in order to resolve the mechanism by which it occurs. They determined that editing entails a series of enzymatic steps rather than the mechanism used in RNA splicing. They also showed that chimeric gRNA-mRNA molecules are aberrant by-products of editing rather than intermediates in the process as had been proposed. Additional studies are exploring precisely how the number of added and deleted uridylates is specified by the gRNA. The Stuart laboratory showed that editing is performed by an aggregation of enzymes that catalyze the separate steps of editing. It also developed a method to purify this multimolecule complex that contains several, perhaps tens of, proteins. This will allow the study of its composition and the functions of its component parts. Indeed, the gene for one component has been identified and its detailed characterization begun. These studies are developing tools to explore related processes. An early finding in the lab was that the various mRNAs are differentially edited during the life cycle of the parasite. The pattern of this editing indicates that editing serves to regulate the alternation between two modes of energy generation. This regulation is coordinated with other events that are occurring during the life c

Animals↗
PubMed1996

Apolipoprotein B RNA editing enzyme-deficient mice are viable despite alterations in lipoprotein metabolism.

RNA editing in the nucleus of higher eukaryotes results in subtle changes to the RNA sequence, with the ability to effect dramatic changes in biological function. The first example to be described and among the best characterized, is the cytidine-to-uridine editing of apolipoprotein B (apo-B) RNA. The editing of apo-B RNA is mediated by a novel cytidine deaminase, apobec-1, which has acquired the ability to bind RNA. The stop translation codon generated by the editing of apo-B RNA truncates the full-length apo-B100 to form apo-B48. The recent observations of tumor formation in Apobec-1 transgenic animals, together with the fact that Apobec-1 is expressed in numerous tissues lacking apo-B, raises the issue of whether this enzyme is essential for a variety of posttranscriptional editing events. To directly test this, mice were created with a null mutation in Apobec-1 using homologous recombination in embryonic stem cells. Mice, homozygous for this mutation, were viable and made apo-B100 but not apo-B48. The null animals were fertile, and a variety of histological, behavioral, and morphological analyses revealed no phenotype other than abnormalities in lipoprotein metabolism, which included an increased low density lipoprotein fraction and a reduction in high density lipoprotein cholesterol. These studies demonstrate that neither apobec-1 nor apo-B48 is essential for viability and suggest that the major role of apobec-1 may be confined to the modulation of lipid transport.

APOBEC-1 Deaminase↗
PubMed1995

RNA editing of a group II intron in Oenothera as a prerequisite for splicing.

The trans-splicing group II intron c/d in the Oenothera mitochondrial nad1 gene is modified by RNA editing in domain 6. This C-to-U conversion generates the typical domain 6 structure, which prompted us to speculate that this RNA editing event might be essential for splicing. To test this hypothesis, we investigated the influence of unedited and edited sequences of the Oenothera intron on splicing in vitro. The stem of domain 6 of intron nad1-c/d was transplanted into the autocatalytic yeast intron aI5c, yielding chimeras with the genomic C and the edited U, respectively, 5' of the branchpoint A. When incubated under self-splicing conditions, only the edited chimera was released as a lariat, while the precursor with the genomically coded C remained inactive. Our results support the hypothesis that Oenothera group II intron nad1-c/d cannot be spliced from the primary transcript without previous editing in domain 6.

Base Sequence↗
PubMed1993

Tissue- and stage-specific modulation of RNA editing of the psbF and psbL transcript from spinach plastids--a new regulatory mechanism?

The psbE operon of spinach chloroplasts, which includes the genes psbE, psbF, psbL and psbJ, encodes two RNA editing sites. One site corresponds to the initiation codon of the psbL transcript, as has been described earlier for the homologous transcript from tobacco, while at a second editing site, newly reported here, an internal phenylalanine codon of the psbF transcript is restored. Both these sites were investigated with respect to the extent of editing in spinach plastids at various developmental stages. The apparent existence of only completely edited transcripts in etioplasts and chloroplasts, indicates that light-induced processes are not acting as determinants in eliciting the editing process. Reduced editing is, however, observed in the psbF and psbL transcript from seeds and roots. This finding suggests that the RNA editing process is differentially down-regulated in leucoplasts and proplastids and that editing may, therefore, function as a regulatory device in plastid gene expression.

Amino Acid Sequence↗
PubMed1995

Quantitation of RNA editing substrates, products and potential intermediates: implications for developmental regulation.

Kinetoplast mitochondrial RNA editing is the developmentally regulated post-transcriptional process of uridine insertion and deletion in mRNAs directed by short guide RNAs (gRNAs), which creates functional mRNAs. Two mechanisms are proposed: transesterification which predicts gRNA/mRNA chimeric intermediates, and enzymatic steps which allow but do not require chimeric intermediates. We quantitated the copy number of apocytochrome b (CYb) gRNAs, edited/unedited mRNAs and gRNA/mRNA chimeras in bloodstream and procyclic form cells of Trypanosoma brucei. Both forms have 35 copies/cell of two gRNAs. Bloodstream forms contain 15 unedited and edited CYb mRNA molecules/cell while procyclic forms have four times as much unedited and over 10 times as much edited mRNA. Chimera levels are very low, 350-5000-fold lower than unedited mRNA or gRNAs, but are over 10 times more abundant in procyclic than bloodstream forms. These results are consistent with chimeras being editing intermediates if their resolution is rapid in respect to their formation, although they could be non-productive byproducts of the editing reaction. Bloodstream chimera sequences differ from procyclic chimeras. These results indicate that developmental regulation is not by gRNA abundance and suggest that it occurs at the level of gRNA utilization possibly by changing abundance of unedited CYb mRNA.

Animals↗
PubMed2000

Evolution of four types of RNA editing in myxomycetes.

The myxomycete Physarum polycephalum requires extensive RNA editing to create functional mitochondrial transcripts. The cytochrome c oxidase subunit 1 (col) transcript exhibits a combination of editing forms not found together in any other eukaryotic RNA: 66 insertions of ribonucleotides (59 Cs, a single U, and three mixed dinucleotides) as well as base conversion of four Cs to Us (Gott et al., J Biol Chem, 1993, 268:25483-25486). Through a phylogenetic survey of col DNA genes and RNA transcripts in representative myxomycetes, we have decoupled the four types of editing in this lineage. Some myxomycetes share insertional editing with P. polycephalum, yet lack C--> U conversion, consistent with previous reports of separation of insertional and base conversion editing in P. polycephalum extracts (Visomirski-Robic & Gott, RNA, 1995, 3:821-837). Most remarkably, we detect unique evolutionary histories of the three different types of insertional editing, though these have been indistinguishable in vitro. For example, Clastoderma debaryanum exhibits insertions of Us, but not Cs or dinucleotides.

Amino Acid Sequence↗
PubMed2003

Serotonin 2C receptors: suicide, serotonin, and runaway RNA editing.

Transcripts of the gene encoding the serotonin 2C receptor are modified by RNA editing, a posttranscriptional process that converts adenosines to inosines. This editing changes up to three genomically encoded amino acids located in the second intracellular loop of the G-protein-coupled receptor. Compared with nonedited receptors, extensively edited receptor isoforms activate G protein less efficiently. Studies on mice revealed that 5-HT2C pre-mRNA editing is regulated in a serotonin-dependent manner, and postmortem studies on brain tissues of patients with schizophrenia and major depression found distinct site-specific alterations of this editing in the prefrontal cortex, a brain region expressing a large number of differently edited 5-HT2C mRNA isoforms. At present, the most complex alterations in 5-HT2C pre-mRNA editing were found in brains of depressed suicide victims. In these brains, 5-HT2C receptor isoforms with reduced function are expressed at significantly increased levels, suggesting that the regulation of editing by synaptic serotonin is defective.

Animals↗
PubMed1995

Genomic organization and chromosomal location of the human dsRNA adenosine deaminase gene: the enzyme for glutamate-activated ion channel RNA editing.

The structure of the human gene encoding the double-stranded RNA (dsRNA) adenosine deaminase (DRADA) was characterized. This nuclear localized enzyme is involved in the RNA editing required for the expression of certain subtypes of glutamate-gated ion channel subunits. The DRADA gene span 30 kb pairs and harbors 15 exons. The transcription of the DRADA gene driven by the putative promoter region, which contains no typical TATA or CCAAT box-like sequences, is initiated at multiple sites, 164 to 216 nucleotides upstream of the translation initiation codon. The three dsRNA binding motifs (DRBM), 70 amino acid residues long, are each encoded by two exons plus an intervening sequence that interrupts the motif at the identical amino acid position. This finding is consistent with the notion that the dsRNA binding domains may be composed of two separate functional subdomains. Fluorescent in situ hybridization localized the DRADA gene on the long arm chromosome 1, region q21. The gene structure and sequence information reported in this study will facilitate the investigation of involvement of DRADA in hereditary diseases that may be the result of malfunction of glutamate-gated ion channels.

Adenosine Deaminase↗
PubMed2004

Analysis of human mRNAs with the reference genome sequence reveals potential errors, polymorphisms, and RNA editing.

The NCBI Reference Sequence (RefSeq) project and the NIH Mammalian Gene Collection (MGC) together define a set of approximately 30,000 nonredundant human mRNA sequences with identified coding regions representing 17,000 distinct loci. These high-quality mRNA sequences allow for the identification of transcribed regions in the human genome sequence, and many researchers accept them as the correct representation of each defined gene sequence. Computational comparison of these mRNA sequences and the recently published essentially finished human genome sequence reveals several thousand undocumented nonsynonymous substitution and frame shift discrepancies between the two resources. Additional analysis is undertaken to verify that the euchromatic human genome is sufficiently complete--containing nearly the whole mRNA collection, thus allowing for a comprehensive analysis to be undertaken. Many of the discrepancies will prove to be genuine polymorphisms in the human population, somatic cell genomic variants, or examples of RNA editing. It is observed that the genome sequence variant has significant additional support from other mRNAs and ESTs, almost four times more often than does the mRNA variant, suggesting that the genome sequence is more accurate. In approximately 15% of these cases, there is substantial support for both variants, suggestive of an undocumented polymorphism. An initial screening against a 24-individual genomic DNA diversity panel verified 60% of a small set of potential single nucleotide polymorphisms from which successful results could be obtained. We also find statistical evidence that a few of these discrepancies are due to RNA editing. Overall, these results suggest that the mRNA collections may contain a substantial number of errors. For current and future mRNA collections, it may be prudent to fully reconcile each genome sequence discrepancy, classifying each as a polymorphism, site of RNA editing or somatic cell variation, or genome sequence error.

Computational Biology↗
PubMed2002

The role of RNA editing by ADARs in RNAi.

Adenosine deaminases that act on RNA (ADARs) are RNA-editing enzymes that deaminate adenosines to create inosines in double-stranded RNA (dsRNA). Here we demonstrate that ADARs are not required for RNA interference (RNAi) and that they do not antagonize the pathway to a detectable level when RNAi is initiated by injecting dsRNA. We find, however, that transgenes expressed in the somatic tissues of wild-type animals are silenced in strains with deletions in the two genes encoding ADARs, adr-1 and adr-2. Transgene-induced gene silencing in adr-1;adr-2 mutants depends on genes required for RNAi, suggesting that a dsRNA intermediate is involved. In wild-type animals we detect edited dsRNA corresponding to transgenes, and we propose that editing of this dsRNA prevents somatic transgenes from initiating RNAi in wild-type animals.

Adenosine Deaminase↗
PubMed1996

The neurofibromatosis type I messenger RNA undergoes base-modification RNA editing.

A functional mooring sequence, known to be required for apolipoprotein B (apoB) mRNA editing, exists in the mRNA encoding the neurofibromatosis type I (NF1) tumor suppressor. Editing of NF1 mRNA modifies cytidine in an arginine codon (CGA) at nucleotide 2914 to a uridine (UGA), creating an in frame translation stop codon. NF1 editing occurs in normal tissue but was several-fold higher in tumors. In vitro editing and transfection assays demonstrated that apoB and NF1 RNA editing will take place in both neural tumor and hepatoma cells. Unlike apoB, NF1 editing did not demonstrate dependence on rate-limiting quantities of APOBEC-1 (the apoB editing catalytic subunit) suggesting that different trans-acting factors may be involved in the two editing processes.

Apolipoproteins B↗
PubMed1994

RNA editing: transfer of genetic information from gRNA to precursor mRNA in vitro.

RNA editing in the mitochondrion of Trypanosoma brucei extensively alters the adenosine triphosphate synthase (ATPase) subunit 6 precursor messenger RNA (pre-mRNA) by addition of 447 uridines and removal of 28 uridines. In vivo, the guide RNA gA6[14] is thought to specify the deletion of two uridines from the editing site closest to the 3' end. In this study, an in vitro system was developed that accurately removed uridines from this editing site in synthetic ATPase 6 pre-mRNA when gA6[14] and ATP were added. Mutations in both the guide RNA and the pre-mRNA editing site suggest that base-pairing interactions control the number of uridines deleted in vitro. Thus, guide RNAs are required for RNA editing and for the transfer of genetic information to pre-mRNAs.

Adenosine Triphosphatases↗