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PubMed2000

Functions and mechanisms of RNA editing.

RNA editing can be broadly defined as any site-specific alteration in an RNA sequence that could have been copied from the template, excluding changes due to processes such as RNA splicing and polyadenylation. Changes in gene expression attributed to editing have been described in organisms from unicellular protozoa to man, and can affect the mRNAs, tRNAs, and rRNAs present in all cellular compartments. These sequence revisions, which include both the insertion and deletion of nucleotides, and the conversion of one base to another, involve a wide range of largely unrelated mechanisms. Recent advances in the development of in vitro editing and transgenic systems for these varied modifications have provided a better understanding of similarities and differences between the biochemical strategies, regulatory sequences, and cellular factors responsible for such RNA processing events.

Amino Acid Sequence↗

PubMedDate not supplied

Expanding genome capacity via RNA editing.

RNA editing, which results in the creation of RNA molecules that differ from the template from which they were made, is a highly specific process. Alterations include converting one base to another, removal of one nucleotide and substitution of another, deletion of encoded residues, and insertion of non-templated nucleotides. Such changes have marked effects on gene expression, ranging from defined amino acid changes to the de novo creation of entire open reading frames. Editing can be regulated in a developmental or tissue-specific manner, and is likely to play a role in the etiology of human disease.

Genetic Techniques↗

PubMed2003

Regulation of ion channel/neurotransmitter receptor function by RNA editing.

RNA editing by select adenosine deamination (A-to-I editing) alters functional determinants in certain ion channels and neurotransmitter receptors in vertebrates and invertebrates. In most cases, edited and unedited versions of a given receptor/channel co-exist to expand the functional space of the receptor population. Recent studies have characterized K(+) channels in squid that are edited at multiple positions, revealed a role for Q/R site editing in AMPA receptor assembly, and demonstrated a link between serotonin levels and the extent of editing of a mammalian serotonin receptor.

Animals↗

PubMed1989

Trypanosomatids: mitochondrial RNA editing.

RNA editing is a genetic regulatory process that was recently discovered in the mitochondrion of trypanosomatid parasites. It alters mRNA by the addition and deletion of uridines. Much remains to be learned about this process, including identification and characterization of the macromolecules that catalyze and regulate this process and the mechanism of editing.

Animals↗

PubMed1997

Both RNA editing and RNA cleavage are required for translation of tobacco chloroplast ndhD mRNA: a possible regulatory mechanism for the expression of a chloroplast operon consisting of functionally unrelated genes.

Tobacco chloroplast genes encoding a photosystem I component (psaC) and a NADH dehydrogenase subunit (ndhD) are transcribed as a dicistronic pre-mRNA which is then cleaved into short mRNAs. An RNA protection assay revealed that the cleavage occurs at multiple sites in the intercistronic region. There are two possible initiation codons in the tobacco ndhD mRNA: the upstream AUG and the AUG created by RNA editing from the in-frame ACG located 25 nt downstream. Using the chloroplast in vitro translation system, we found that translation begins only from the edited AUG. The extent of ACG to AUG editing is partial and depends on developmental and environmental conditions. In addition, the in vitro assay showed that the psaC/ndhD dicistronic mRNA is not functional and that the intercistronic cleavage is a prerequisite for both ndhD and psaC translation. Using a series of mutant mRNAs, we showed that an intramolecular interaction between an 8 nt sequence in the psaC coding region and its complementary 8 nt sequence in the 5' ndhD UTR is the negative element for translation of the dicistronic mRNA. A possible mechanism in which the differential expression of the chloroplast operon consists of functionally unrelated genes is discussed.

Chloroplasts↗

PubMed1994

Developmental regulation of RNA editing and polyadenylation in four life cycle stages of Trypanosoma congolense.

The accumulation of many edited mRNAs is developmentally regulated in a transcript-specific fashion in Trypanosoma brucei. In addition, these transcripts are frequently present in two size classes which differ substantially in the lengths of their poly(A) tails, and poly(A) tail length is also developmentally regulated. Previously, these phenomena have only been studied in the mammalian bloodstream and insect procyclic forms (BF and PF, respectively) of T. brucei. In this paper, we examine developmental regulation of edited RNA abundance and poly(A) tail length of 3 mitochondrially encoded RNAs in mammalian BF and 3 insect stages (PF, epimastigotes, and metacyclics) of T. congolense. T. congolense BF and PF are similar, but not identical, to these stages of T. brucei with regard to edited RNA accumulation and poly(A) tail length. At the level of edited RNA, both epimastigotes and metacyclic stage parasites appear to be pre-adapted for the respiratory mechanisms of BF but not yet down-regulated from the cytochrome-based respiration of PF since edited RNAs encoding NADH dehydrogenase components are up-regulated and edited CYb RNA is abundant in these stages. Poly(A) tail lengths of mitochondrial mRNAs appear to be regulated independently of edited RNA abundance. These results indicate that multiple mechanisms for regulation of mitochondrial gene expression are active throughout the trypanosome life cycle.

Animals↗

PubMed1998

Site-selective inhibition of plastid RNA editing by heat shock and antibiotics: a role for plastid translation in RNA editing.

RNA editing in higher plant plastids changes single cytidine residues to uridine through an unknown mechanism. In order to investigate the relation of editing to physiological processes and to other steps in plastid gene expression, we have tested the sensitivity of chloroplast RNA editing to heat shock and antibiotics. We show that heat shock conditions as well as treatment of plants with prokaryotic translational inhibitors can inhibit plastid RNA editing. Surprisingly, this inhibitory effect is confined to a limited number of plastid editing sites suggesting that some site-specific factor(s) but none of the general components of the plastid RNA editing machinery are compromised. Contrary to previous expectations, our results provide evidence for a role of plastid translation in RNA editing.

Anti-Bacterial Agents↗

PubMedDate not supplied

Diversity and evolution of mitochondrial RNA editing systems.

'RNA editing' describes the programmed alteration of the nucleotide sequence of an RNA species, relative to the sequence of the encoding DNA. The phenomenon encompasses two generic patterns of nucleotide change, 'insertion/deletion' and 'substitution', defined on the basis of whether the sequence of the edited RNA is colinear with the DNA sequence that encodes it. RNA editing is mediated by a variety of pathways that are mechanistically and evolutionarily unrelated. Messenger, ribosomal, transfer and viral RNAs all undergo editing in different systems, but well-documented cases of this phenomenon have so far been described only in eukaryotes, and most often in mitochondria. Editing of mRNA changes the identity of encoded amino acids and may create translation initiation and termination codons. The existence of RNA editing violates one of the long-accepted tenets of genetic information flow, namely, that the amino acid sequence of a protein can be directly predicted from the corresponding gene sequence. Particular RNA editing systems display a narrow phylogenetic distribution, which argues that such systems are derived within specific eukaryotic lineages, rather than representing traits that ultimately trace to a common ancestor of eukaryotes, or even further back in evolution. The derived nature of RNA editing raises intriguing questions about how and why RNA editing systems arise, and how they become fixed as additional, essential steps in genetic information transfer.

Amino Acid Sequence↗

PubMed2001

Four related proteins of the Trypanosoma brucei RNA editing complex.

RNA editing in kinetoplastid mitochondria occurs by a series of enzymatic steps that is catalyzed by a macromolecular complex. Four novel proteins and their corresponding genes were identified by mass spectrometric analysis of purified editing complexes from Trypanosoma brucei. These four proteins, TbMP81, TbMP63, TbMP42, and TbMP18, contain conserved sequences to various degrees. All four proteins have sequence similarity in the C terminus; TbMP18 has considerable sequence similarity to the C-terminal region of TbMP42, and TbMP81, TbMP63, and TbMP42 contain zinc finger motif(s). Monoclonal antibodies that are specific for TbMP63 and TbMP42 immunoprecipitate in vitro RNA editing activities. The proteins are present in the immunoprecipitates and sediment at 20S along with the in vitro editing, and RNA editing ligases TbMP52 and TbMP48. Recombinant TbMP63 and TbMP52 coimmunoprecipitate. These results indicate that these four proteins are components of the RNA editing complex and that TbMP63 and TbMP52 can interact.

Amino Acid Motifs↗

PubMed2001

Trypanosome RNA editing: simple guide RNA features enhance U deletion 100-fold.

Trypanosome RNA editing is a massive processing of mRNA by U deletion and U insertion, directed by trans-acting guide RNAs (gRNAs). A U deletion cycle and a U insertion cycle have been reproduced in vitro using synthetic ATPase (A6) pre-mRNA and gRNA. Here we examine which gRNA features are important for this U deletion. We find that, foremost, this editing depends critically on the single-stranded character of a few gRNA and a few mRNA residues abutting the anchor duplex, a feature not previously appreciated. That plus any base-pairing sequence to tether the upstream mRNA are all the gRNA needs to direct unexpectedly efficient in vitro U deletion, using either the purified editing complex or whole extract. In fact, our optimized gRNA constructs support faithful U deletion up to 100 times more efficiently than the natural gRNA, and they can edit the majority of mRNA molecules. This is a marked improvement of in vitro U deletion, in which previous artificial gRNAs were no more active than natural gRNA and the editing efficiencies were at most a few percent. Furthermore, this editing is not stimulated by most other previously noted gRNA features, including its potential ligation bridge, 3' OH moiety, any U residues in the tether, the conserved structure of the central region, or proteins that normally bind these regions. Our data also have implications about evolutionary forces active in RNA editing.

Animals↗

PubMed1998

Analysis of protein complexes assembled on apolipoprotein B mRNA for mooring sequence-dependent RNA editing.

Apolipoprotein B (apoB) mRNA editing involves a cytidine-to-uridine transition at a select site catalyzed by a cytidine deaminase known as APOBEC-1. This enzyme cannot edit RNA alone but acquires site-specific editing capacity in the context of additional protein factors (auxiliary proteins). These proteins are currently hypothesized to assemble with APBEC-1 as a holoenzyme complex or editosome. Auxiliary proteins are the focus of ongoing research as they presumably serve important structural and regulatory roles in the editosome. The abilities of auxiliary proteins to interact with APOBEC-1 and apoB RNA and to promote RNA editing activity are important endpoints used as proof that proteins are functionally involved in apoB RNA editing. This article reviews the discovery of the editosome and provides detailed protocols for its isolation and subfractionation.

APOBEC-1 Deaminase↗

PubMed1997

RNA editing: getting U into RNA.

RNA editing in kinetoplastid protozoa remodels the sequences of mitochondrial pre-mRNAs by the precise insertion and deletion of uridylate residues. These sequence changes are directed by small trans-acting RNAs, termed guide RNAs. The basic mechanistic pathway by which edited RNA is generated has recently been elucidated using in vitro systems capable of a full round of guide-RNA-directed editing.

Base Sequence↗

PubMed2005

Molecular determinants and guided evolution of species-specific RNA editing.

Most RNA editing systems are mechanistically diverse, informationally restorative, and scattershot in eukaryotic lineages. In contrast, genetic recoding by adenosine-to-inosine RNA editing seems common in animals; usually, altering highly conserved or invariant coding positions in proteins. Here I report striking variation between species in the recoding of synaptotagmin I (sytI). Fruitflies, mosquitoes and butterflies possess shared and species-specific sytI editing sites, all within a single exon. Honeybees, beetles and roaches do not edit sytI. The editing machinery is usually directed to modify particular adenosines by information stored in intron-mediated RNA structures. Combining comparative genomics of 34 species with mutational analysis reveals that complex, multi-domain, pre-mRNA structures solely determine species-appropriate RNA editing. One of these is a previously unreported long-range pseudoknot. I show that small changes to intronic sequences, far removed from an editing site, can transfer the species specificity of editing between RNA substrates. Taken together, these data support a phylogeny of sytI gene editing spanning more than 250 million years of hexapod evolution. The results also provide models for the genesis of RNA editing sites through the stepwise addition of structural domains, or by short walks through sequence space from ancestral structures.

Adenosine↗

PubMed1993

RNA editing of rapeseed mitochondrial atp9 transcripts: RNA editing changes four amino acids, but termination codon is already encoded by genomic sequence.

The gene encoding subunit 9 of Fo-ATPase of rapeseed mitochondria has been isolated. The complete genomic DNA sequence and cDNA sequence corresponding to the atp9 gene transcript have been determined by a method involving cDNA synthesis, using specific oligonucleotides as primers, followed by PCR amplification, cloning and sequencing of the amplification products. In comparison of cDNA sequences to genomic one, four modifications, C-to-U conversions, have been found. When compared with RNA editing patterns of atp9 transcripts among plant mitochondria, that of rapeseed atp9 transcript is more simple; there are only four editing sites on the coding region, and its termination codon is already encoded by genomic sequence.

Amino Acid Sequence↗

PubMed1996

In vivo dissection of cis-acting determinants for plastid RNA editing.

Substitutional RNA editing changes single C nucleotides in higher plant chloroplast transcripts into U residues. To determine the cis-acting sequence elements involved in plastid RNA editing, we constructed a series of chloroplast transformation vectors harboring selected editing sites of the tobacco ndhB transcript in a chimeric context. The constructs were inserted into the tobacco plastid genome by biolistic transformation leading to the production of stable chimeric RNAs. Analysis of RNA editing revealed unexpected differences in the size of the essential cis elements or in their distance from the editing site. Flanking sequences of identical size direct virtually complete editing for one pair of editing sites, partial editing for a second and no editing at all for a third pair of sites. Serial 5' and 3' deletions allowed us to define the cis-acting elements more precisely and to identify a sequence element essential for editing site recognition. In addition, a single nucleotide substitution immediately upstream of an editing position was introduced. This mutation was found drastically and selectively to reduce the editing efficiency of the downstream editing site, demonstrating that position -1 is important for either site recognition or catalysis. Our results indicate that the editing of adjacent sites is likely to be mechanistically coupled. In no case did the presence in the plastome of the additional editing sites have any effect on the editing efficiency of the endogenous ndhB sites, indicating that the availability of site-specific trans-acting factors is not rate limiting.

Base Sequence↗

PubMed2004

RNA editing (R/G site) and flip-flop splicing of the AMPA receptor subunit GluR2 in nervous tissue of epilepsy patients.

Editing and alternative splicing of mRNA are posttranscriptional steps probably involved in pathophysiological aspects of epilepsy. The present study analyses the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunit GluR2 with respect to the expression of (i) editing at the R/G site and (ii) flip-flop cassettes. Nervous tissue from patients with temporal lobe epilepsy was analysed by RT-PCR followed by restriction enzyme assays. Human autoptic tissue served as control. R/G editing status: the relative amount of edited RNA was significantly increased in the hippocampal tissue, whereas no changes were found in neocortical tissues. Flip-flop expression: no significant alterations were found in relative abundance of spliced variants containing the flip exon. The increased editing at the R/G site in the hippocampal tissue of epilepsy patients may enhance responses to glutamate, resulting in a synapse operating at an increased gain.

Adolescent↗

PubMed2001

Association of two novel proteins, TbMP52 and TbMP48, with the Trypanosoma brucei RNA editing complex.

RNA editing in kinetoplastid mitochondria inserts and deletes uridylates at multiple sites in pre-mRNAs as directed by guide RNAs. This occurs by a series of steps that are catalyzed by endoribonuclease, 3'-terminal uridylyl transferase, 3'-exouridylylase, and RNA ligase activities. A multiprotein complex that contains these activities and catalyzes deletion editing in vitro was enriched from Trypanosoma brucei mitochondria by sequential ion-exchange and gel filtration chromatography, followed by glycerol gradient sedimentation. The complex size is approximately 1,600 kDa, and the purified fraction contains 20 major polypeptides. A monoclonal antibody that was generated against the enriched complex reacts with an approximately 49-kDa protein and specifically immunoprecipitates in vitro deletion RNA editing activity. The protein recognized by the antibody was identified by mass spectrometry, and the corresponding gene, designated TbMP52, was cloned. Recombinant TbMP52 reacts with the monoclonal antibody. Another novel protein, TbMP48, which is similar to TbMP52, and its gene were also identified in the enriched complex. These results suggest that TbMP52 and TbMP48 are components of the RNA editing complex.

Amino Acid Sequence↗

PubMed1999

RNA editing.

The term RNA editing describes those molecular processes in which the information content is altered in an RNA molecule. To date such changes have been observed in tRNA. rRNA and mRNA molecules of eukaryotes, but not prokaryotes. The demonstration of RNA editing in prokaryotes may only be a matter of time, considering the range of species in which the various RNA editing processes have been found. RNA editing occurs in the nucleus, as well as in mitochondria and plastids, which are thought to have evolved from prokaryotic-like endosymbionts. Most of the RNA editing processes, however, appear to be evolutionarily recent acquisitions that arose independently. The diversity of RNA editing mechanisms includes nucleoside modifications such as C to U and A to I deaminations, as well as non-templated nucleotide additions and insertions. RNA editing in mRNAs effectively alters the amino acid sequence of the encoded protein so that it differs from that predicted by the genomic DNA sequence.

Amino Acid Sequence↗