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PubMed1997

Localization of a novel human RNA-editing deaminase (hRED2 or ADARB2) to chromosome 10p15.

RNA-editing deaminase 2 (RED2; ADARB2) is a newly identified potential double-stranded RNA adenosine deaminase. It is the third member of this family, which includes DRADA and RED1. Genes of this family are candidates for involvement in neurological diseases such as epilepsy, because of their expression patterns and described functions. All three described genes are well expressed in brain, and DRADA and RED1 have been shown to play a role in the editing of mRNAs coding for glutamate receptor subunits in vitro, thereby changing the properties of these channels, which are the main excitatory neurotransmitter receptors in brain. Here we report the mapping of the human RED2 (hRED2; ADARB2) gene. Using the sequence of rat RED2, we identified a homologous human expressed sequence tag, and subsequently designed primers in the 3' untranslated region of the hRED2 transcript to perform polymerase chain reaction amplification on two somatic cell hybrid mapping panels. This allowed us to localize hRED2 on chromosome 10p15; until now, no genetic diseases have been mapped in this region or in the syntenic mouse chromosomal region that may involve RED2.

Adenosine Deaminase↗
PubMed2026

Comparative chloroplast genomics of six Bupleurum (Apiaceae) accessions: candidate barcodes, phylogeny based on available plastomes, and candidate RNA-editing sites.

INTRODUCTION: Bupleurum L. (Apiaceae), a taxonomically intricate genus of about 190 species and a source of Radix Bupleuri (Chai Hu), is difficult to discriminate because of convergent morphology, infraspecific variation, and limited genomic sampling. This study aimed to characterize plastome variation, identify and validate candidate molecular markers, reconstruct plastid phylogenetic relationships, and assess candidate plastid RNA-editing sites in Bupleurum. METHODS: We assembled six plastomes from subgenus Bupleurum, screened 51 Bupleurum plastomes for diagnostic loci, reconstructed whole-plastome and partitioned protein-coding-sequence phylogenies, and predicted plastid C-to-U RNA-editing candidates across the six newly assembled plastomes using a PREP-Cp-compatible workflow. Candidate barcode performance was evaluated against the reference plastome phylogenies, and codon-based models were used to test for positive selection. RESULTS: The plastomes were 154,496-155,778 bp with the canonical quadripartite structure and GC contents of 37.67-37.73%. Gene content was stable (131-132 genes; 86-87 protein-coding genes); B. falcatum subsp. cernuum lacked ycf15 but contained an additional inverted-repeat-associated ycf1 annotation. A/U-ending synonymous codons were favoured. Finite pairwise Ka/Ks estimates were below 1 for most genes, and site-specific codon models detected no positive selection. Each plastome contained 55-61 pure microsatellites, dominated by A/T mononucleotide motifs. MarkerSeek ranked 265 features and identified atpF-atpH, petA-psbJ, rpl32-trnL-UAG, and ycf1 as leading candidate barcodes. ycf1 recovered 38 of 41 nodes strongly supported by both reference trees, whereas a partitioned four-locus analysis recovered 40 of 41 and distinguished all 51 accession sequences. However, only one of seven multi-accession operational binomial groups was monophyletic, and only one showed a positive local barcode gap. The whole-plastome phylogeny recovered Bupleurum as monophyletic relative to Chamaesium. The two sampled Penninervia accessions occupied early-diverging positions without forming an exclusive clade. B. falcatum subsp. cernuum was sister to B. ranunculoides, with B. ranunculoides subsp. telonense sister to that pair. A partitioned 74-CDS analysis recovered the same key relationships and 45 of 50 internal bipartitions. Across the six newly assembled plastomes, 57-63 nonsynonymous C-to-U candidates were predicted per accession (367 total) in 21-22 genes; 269 affected the second codon position and 98 the first. DISCUSSION: Bupleurum plastomes are structurally conservative but retain localised divergence useful for marker development. Concordant whole-plastome and CDS genealogies support genus monophyly, whereas sparse Penninervia sampling and maternal plastid inheritance preclude rejecting traditional subgeneric classification. The predicted RNA-editing sites represent candidates for future experimental validation rather than an established Bupleurum editome. These genomic resources support authentication, conservation, and evolutionary research in Bupleurum.

Apiaceae↗
PubMed2000

The mle(napts) RNA helicase mutation in drosophila results in a splicing catastrophe of the para Na+ channel transcript in a region of RNA editing.

The mle(napts) mutation causes temperature-dependent blockade of action potentials resulting from decreased abundance of para-encoded Na+ channels. Although maleless (mle) encodes a double-stranded RNA (dsRNA) helicase, exactly how mle(napts) affects para expression remained uncertain. Here, we show that para transcripts undergo adenosine-to-inosine (A-to-I) RNA editing via a mechanism that apparently requires dsRNA secondary structure formation encompassing the edited exon and the downstream intron. In an mle(napts) background, >80% of para transcripts are aberrant, owing to internal deletions that include the edited exon. We propose that the Mle helicase is required to resolve the dsRNA structure and that failure to do so in an mle(napts) background causes exon skipping because the normal splice donor is occluded. These results explain how mlen(napts) affects Na+ channel expression and provide new insights into the mechanism of RNA editing.

Action Potentials↗
PubMed1990

RNA editing of wheat mitochondrial ATP synthase subunit 9: direct protein and cDNA sequencing.

RNA editing of subunit 9 of the wheat mitochondrial ATP synthase has been studied by cDNA and protein sequence analysis. Most of the cDNA clones sequenced (95%) showed that editing by C-to-U transitions occurred at eight positions in the coding region. Consequently, 5 amino acids were changed in the protein when compared with the sequence predicted from the gene. Two edited codons gave no changes (silent editing). One of the C-to-U transitions generated a stop codon by modifying the arginine codon CGA to UGA. Thus, the protein produced is 6 amino acids shorter than that deduced from the genomic sequence. Minor forms of cDNA with partial or overedited sequences were also found. Protein sequence and amino acid composition analyses confirmed the results obtained by cDNA sequencing and showed that the major form of edited atp9 mRNA is translated.

Adenosine Triphosphatases↗
PubMed2001

Q/R RNA editing of the AMPA receptor subunit 2 (GRIA2) transcript evolves no later than the appearance of cartilaginous fishes.

The amino acid, either a glutamine (Q) or an arginine (R), at the Q/R site of the pore-lining segment (M2) of a vertebrate AMPA receptor subunit critically influences the properties of the receptor. The R codon of the mammalian AMPA receptor subunit 2 (GRIA2) transcript is not coded by the chromosomal sequence, but is created by posttranscriptional RNA editing activities. On the other hand, the R codons of some teleost GRIA2 homologs are coded by chromosomal sequences. To elucidate the evolution of the utilization of Q/R RNA editing in modifying vertebrate GRIA2 transcripts, the GRIA2 genes of five fish species and an amphibian were studied. The putative hagfish GRIA2 homolog (hfGRIA2) encodes an R codon, whereas shark and bullfrog GRIA2 genes specify a Q codon at the genomic Q/R site. All gnathostoma GRIA2 genes possess an intron splitting the coding regions of M2 and the third hydrophobic region (M3). The intronic components required for Q/R RNA editing are preserved in all the Q-coding vertebrate GRIA2 genes but are absent from the R-coding GRIA2 genes. Interestingly, the hfGRIA2 is intronless, suggesting that hfGRIA2 is unlikely evolved from a Q/R editing-competent gene. Results of this study suggest that modification of GRIA2 transcripts by Q/R editing is most likely acquired after the separation of the Agnatha and Gnathostome.

Animals↗
PubMed2005

Chromosomal storage of the RNA-editing enzyme ADAR1 in Xenopus oocytes.

ADARs (adenosine deaminases that act on RNA) are RNA-editing enzymes that convert adenosines to inosines in structured or double-stranded RNAs. Expression and intracellular distribution of ADAR1 is controlled by a plethora of mechanisms suggesting that enzyme activity has to be tightly regulated. Mammalian ADAR1 is a shuttling protein, whereas Xenopus ADAR1 is exclusively nuclear. In oocytes, Xenopus ADAR1 associates with most nascent transcripts but is strongly enriched at a specific site on chromosome 3, termed the special loop. Enrichment at this site requires the presence of RNAs but is independent of ongoing transcription. Here we show that RNAs transcribed elsewhere in the genome accumulate at the special loop even in the absence of transcription. In situ hybridization experiments, however, indicate the absence of known editing substrates from this site. In the absence of transcription also other RNA binding and processing factors accumulate at the special loop, suggesting that ADAR1 is stored or assembled at the special loop in an RNA-containing complex. Nuclear injection of RNAs providing binding sites for ADAR1 dissociates the enzyme from the special loop, supporting the notion that the special loop represents a site where ADAR1 is stored, possibly for later use during development.

Adenosine Deaminase↗
PubMed2003

RNA-editing cytidine deaminase Apobec-1 is unable to induce somatic hypermutation in mammalian cells.

Antibody diversification by somatic hypermutation, gene conversion, and class switch recombination is completely dependent on activation-induced cytidine deaminase (AID). A recent report showing induction of DNA mutations in Escherichia coli by overexpression of AID, Apobec-1, and related members of the RNA-editing cytidine deaminase family suggested that they may directly modify deoxycytidine in DNA in mammalian cells (DNA-editing model). We therefore examined whether Apobec-1 bona fide RNA-editing enzyme could show somatic hypermutation and class switching activities in murine B lymphocytes and fibroblasts. Unlike AID, Apobec-1 was unable to induce somatic hypermutation or class switching. The results force a reevaluation of the physiological significance of the DNA deaminase activities of AID and Apobec-1 in E. coli and in vitro.

3T3 Cells↗
PubMed2001

RNA editing of the 5-HT(2C) receptor is reduced in schizophrenia.

5-HT(2C) receptor (5HT(2C)R, serotonin-2C) RNA undergoes editing to produce several receptor variants, some with pharmacological differences. This investigation comprised two parts: the characterisation of 5-HT(2C)R RNA editing in a larger human control sample than previously examined, and a comparative study in subjects with schizophrenia. Secondary structure analysis of the putative edited region of the human 5-HT(2C)R gene predicted the existence of a double stranded (ds) RNA loop, essential for RNA editing in this receptor. RNA was then extracted from frontal cortex of five controls and five subjects with schizophrenia. RT-PCR products of the edited region were cloned and sequenced (n = 100). Reduced RNA editing, increased expression of the unedited 5-HT(2C-INI) isoform in schizophrenia (P = 0.001) and decreased expression of the 5-HT(2C-VSV) and 5-HT(2C-VNV) isoforms were detected in the schizophrenia group. In addition, two novel mRNA edited variants were identified: 5-HT(2C-MNI) and 5-HT(2C-VDI). Screening of the 5-HT(2C)R gene did not reveal any mutations likely to disrupt the dsRNA loop, suggesting that the reduced RNA editing in schizophrenia may instead be caused by altered activity of the editing enzyme(s). Since the unedited 5-HT(2C-INI) is more efficiently coupled to G proteins than the other isoforms, its increased expression in schizophrenia may lead to enhanced 5-HT(2C)R-mediated effects. The results also illustrate that potentially important receptor alterations may occur in schizophrenia which are not detectable merely in terms of receptor abundance.

Animals↗
PubMed2001

An RNA ligase essential for RNA editing and survival of the bloodstream form of Trypanosoma brucei.

RNA editing in trypanosomes occurs by a series of enzymatic steps that are catalyzed by a macromolecular complex. The TbMP52 protein is shown to be a component of this complex, to have RNA ligase activity, and to be one of two adenylatable proteins in the complex. Regulated repression of TbMP52 blocks editing, which shows that it is a functional component of the editing complex. This repression is lethal in bloodforms of the parasite, indicating that editing is essential in the mammalian stage of the life cycle. The editing complex, which is present in all kinetoplastid parasites, may thus be a chemotherapeutic target.

Amino Acid Sequence↗
PubMed2001

Conformational changes that occur during an RNA-editing adenosine deamination reaction.

ADARs are adenosine deaminases responsible for RNA-editing reactions that occur within duplex RNA. Currently little is known regarding the nature of the protein-RNA interactions that lead to site-selective adenosine deamination. We previously reported that ADAR2 induced changes in 2-aminopurine fluorescence of a modified substrate, consistent with a base-flipping mechanism. Additional data have been obtained using full-length ADAR2 and a protein comprising only the RNA binding domain (RBD) of ADAR2. The increase in 2-aminopurine fluorescence is specific to the editing site and dependent on the presence of the catalytic domain. Hydroxyl radical footprinting demonstrates that the RBD protects a region of the RNA duplex around the editing site, suggesting a significant role for the RBD in identifying potential ADAR2 editing sites. Nucleotides near the editing site on the non-edited strand become hypersensitive to hydrolytic cleavage upon binding of ADAR2 RBD. Therefore, the RBD may assist base flipping by increasing the conformational flexibility of nucleotides in the duplex adjacent to its binding site. In addition, an increase in tryptophan fluorescence is observed when ADAR2 binds duplex RNA, suggesting a conformational change in the catalytic domain of the enzyme. Furthermore, acrylamide quenching experiments indicate that RNA binding creates heterogeneity in the solvent accessibility of ADAR2 tryptophan residues, with one out of five tryptophans more solvent-accessible in the ADAR2.RNA complex.

2-Aminopurine↗
PubMed1997

RNA editing generates a diverse array of transcripts encoding squid Kv2 K+ channels with altered functional properties.

We have cloned a Kv2 potassium channel from squid optic lobe termed sqKv2. Multiple overlapping sqKv2 cDNA clones differed from one another at specific positions by purine transitions. To test whether the purine transitions were generated by RNA editing, we compared a 360 nucleotide genomic sequence with corresponding cDNA sequences (encoding S4-S6) isolated from individual animals and lying on a single gene and exon. cDNA sequences differed from genomic sequence at 17 positions, resulting in 28 unique sequences. There was invariantly an adenosine in the genomic sequence and a guanosine in the edited cDNA sequences. Two of the edits altered the rates of channel closure and slow inactivation. These results extend selective RNA editing to invertebrate taxa and represents a novel mechanism for the posttranscriptional modulation of voltage-gated ion channels.

Adenine↗
PubMed2005

In Trypanosoma brucei RNA editing, band II enables recognition specifically at each step of the U insertion cycle.

Trypanosome RNA editing is the posttranscriptional insertion and deletion of uridylate (U) residues, often to a massive extent, through cycles of cleavage, U addition or U removal, and ligation. These editing cycles are catalyzed by a complex that we purified to seven major proteins (bands I through VII). Here we analyze the role of band II using extracts of clonal band II RNA interference (RNAi) cell lines prepared by a rapid protocol that enables retention of activities that are lost during traditional extract preparation. By individually scoring each step of editing, we show that band II is critical for all steps of U insertion but is not important for any of the steps of U deletion or for their coordination into the U deletion cycle. This specificity supports the long- standing model that U-insertional and U-deletional activities are separated within the editing complex. Furthermore, by assaying the basic activities of the enzymes that catalyze the steps of U insertion, independent of their action in editing, we show that band II is not any of those enzymes. Rather, band II enables endonuclease action at authentic U insertion sites, terminal-uridylyl-transferase (TUTase) action at cleaved U insertion sites, and U-insertion-specific ligase (band V/IREL) action in the editing complex. Thus, band II facilitates each step of U insertion by providing proper RNA and/or protein recognition. We propose that band II (TbMP81) be called IRER, indicating its essential nature in U-insertional RNA editing recognition.

Animals↗
PubMed1997

Mitochondrial mRNA 3' cleavage/polyadenylation and RNA editing in Trypanosoma brucei are independent events.

The organization of the mitochondrial maxicircle genome of Trypanosoma brucei is unique in the close packing of the mRNA genes. For many of them, the 5' and 3' ends of adjacent transcripts overlap and formation of the proper 3' or 5' end can eliminate a portion of the coding sequence of the adjacent gene. Large, polycistronic transcripts have been detected. suggesting that mechanisms for precise cleavages at both 5' and 3' gene boundaries must exist. However, no common sequences near the ends of the mRNAs that could be candidates for control regions have been detected. In addition, nothing is known about how RNA editing interacts with and affects 5' and 3' processing and/or polyadenylation. Edited precursor transcripts have been detected, indicating that editing complexes can assemble prior to transcript cleavage. Because editing often initiates near the 3' end of the mRNA, the assembly of an editing complex in this region may influence the cleavage selection process. In order to determine the extent that RNA editing and 3' end-processing interact, RNAs were analyzed to determine the extent of editing in precursor RNAs and to determine if unedited transcripts can be cleaved and polyadenylated. Two overlapping RNA junctions were analyzed; the junction between NADH dehydrogenase (ND) subunit 7 and cytochrome oxidase (CO) subunit III, and the junction between CO subunit II and maxicircle unidentified reading frame (MURF) II. For both of these RNAs, editing affects restriction endonuclease recognition sequences, allowing us to analyze editing patterns by differential restriction digests. These analyses suggest that when the gRNA is supplied in trans, RNA editing and cleavage/polyadenylation are independent events and while they may influence one another, one event is not dependent on the other. Conversely, for the COII transcript, where the gRNA is located at the 3' end of the mRNA and appears to be supplied in cis, edited precursors were not detected. This suggests a requirement for a precise intramolecular interaction for COII editing that cannot form prior to 3' end-maturation.

Animals↗
PubMed1996

RNA editing changes the identity of a mitochondrial tRNA in marsupials.

In the mitochondrial genome of marsupials, the tRNA gene located at the position where in other mammals an aspartyl-tRNA is encoded carries the glycine anticodon GCC. Post-transcriptionally, an RNA editing mechanism affects the second position of the anticodon such that the aspartate anticodon GUC is created in approximately 50% of the mature tRNA pool. We show that the unedited version of this tRNA'Asp' (GCC) can be specifically aminoacylated with glycine in vitro, while the edited version becomes aminoacylated with aspartic acid. Furthermore, we show that both forms are aminoacylated to a substantial extent in vivo. By replacing an amino group with a keto group, RNA editing thus changes the identity of this tRNA allowing a single gene to encode two tRNAs.

Animals↗
PubMed1994

Control of kinetic properties of AMPA receptor channels by nuclear RNA editing.

AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor channels mediate the fast component of excitatory postsynaptic currents in the central nervous system. Site-selective nuclear RNA editing controls the calcium permeability of these channels, and RNA editing at a second site is shown here to affect the kinetic aspects of these channels in rat brain. In three of the four AMPA receptor subunits (GluR-B, -C, and -D), intronic elements determine a codon switch (AGA, arginine, to GGA, glycine) in the primary transcripts in a position termed the R/G site, which immediately precedes the alternatively spliced modules "flip" and "flop." The extent of editing at this site progresses with brain development in a manner specific for subunit and splice form, and edited channels possess faster recovery rates from desensitization.

Alternative Splicing↗
PubMed2004

RNA editing of a miRNA precursor.

Micro RNAs comprise a large family of small, functional RNAs with important roles in the regulation of protein coding genes in animals and plants. Here we show that human and mouse miRNA22 precursor molecules are subject to posttranscriptional modification by A-to-I RNA editing in vivo. The observed editing events are predicted to have significant implications for the biogenesis and function of miRNA22 and might point toward a more general role for RNA editing in the regulation of miRNA gene expression.

Animals↗