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PubMed1996

RNA editing in plant mitochondria and chloroplasts.

In the mitochondria and chloroplasts of higher plants there is an RNA editing activity responsible for specific C-to-U conversions and for a few U-to-C conversions leading to RNA sequences different from the corresponding DNA sequences. RNA editing is a post-transcriptional process which essentially affects the transcripts of protein coding genes, but has also been found to modify non-coding transcribed regions, structural RNAs and intron sequences. RNA editing is essential for correct gene expression: proteins translated from edited transcripts are different from the ones deduced from the genes sequences and usually present higher similarity to the corresponding non-plant homologues. Initiation and stop codons can also be created by RNA editing. RNA editing has also been shown to be required for the stabilization of the secondary structure of introns and tRNAs. The biochemistry of RNA editing in plant organelles is still largely unknown. In mitochondria, recent experiments indicate that RNA editing may be a deamination process. A plastid transformation technique showed to be a powerful tool for the study of RNA editing. The biochemistry as well as the evolutionary features of RNA editing in both organelles are compared in order to identify common as well as organelle-specific components.

Amino Acid Sequence↗

PubMed2006

dbRES: a web-oriented database for annotated RNA editing sites.

Although a large amount of experimentally derived information about RNA editing sites currently exists, this information has remained scattered in a variety of sources and in diverse data formats. Availability of standard collections for high-quality experimental data will be by of great help for systematic studying of RNA editing, especially for developing computational algorithm to predict RNA editing site. dbRES (http://bioinfo.au.tsinghua.edu.cn/dbRES) is a public database of known RNA editing sites. All sites are manually curated from literature and GenBank annotations. dbRES version 1.1 contains 5437 RNA editing sites of 251 transcripts, covering 96 organisms across plant, metazoan, protozoa, fungi and virus. dbRES provides comprehensive annotations and data summaries, including (but not limited to) transcript sequences, RNA editing types, editing site locations, amino acid changes, organisms, subcellular organelles (if available), cited references, etc. A user-friendly web interface is developed to facilitate both retrieving data and online display of RNA edit site information.

Databases, Nucleic Acid↗

PubMed2003

Hydrolytic nucleoside and nucleotide deamination, and genetic instability: a possible link between RNA-editing enzymes and cancer?

Post-transcriptional RNA editing generates novel gene products by changing the coding sequence of the transcript from that in the genome. Two classes of RNA editing exist in mammals, each of which involves an enzymatic deamination. These reactions have stringent sequence and structural requirements for their target RNAs, and each requires distinctive enzymatic machinery. Alterations in the expression or abundance of RNA-editing factors produce unanticipated alterations in the processing or expression of RNAs, in some cases outside their physiological targets. Recent findings suggest that unregulated expression of the cytidine-deaminase gene family might lead to deamination of deoxycytidine nucleotides in DNA. Aberrant or dysregulated RNA editing, or altered expression of editing factors, might contribute to genomic instability in cancer.

Animals↗

PubMed1996

Effects of RNA editing and gene processing on phylogenetic reconstruction.

RNA editing is a ubiquitous phenomenon affecting most mitochondrial and chloroplast, and some nuclear genomes, where mutations in genomic DNA are "corrected" in the mRNA during transcriptional processing. Most editing in plants and animals corrects T-to-C substitutions at nonsynonymous first or second base positions, and the overall effect is an mRNA and protein sequence that differs from that predicted by the DNA. It has been suggested that genomic sequences that undergo editing should not be used in phylogenetics. We contend that editing will have little or no effect on DNA-based phylogenetic reconstruction because it is an intrinsic transcriptional process that does not affect the historical information in the DNA sequence. The only effect of editing on protein-coding DNA should be an increase in the rate of T-to-C transitions. Here we test the effects of RNA editing on phylogenetic reconstruction, using two data sets with high levels of editing, plant coxII and coxIII. Even with high levels of editing, phylogenies based on DNA and edited mRNA are virtually identical. The two types of sequences should not be used in the same analysis, however, because the particular forms of the gene will tend to group together. We also examine the effects of processed paralogs--a term proposed for mRNA sequences that are reverse transcribed and reinserted into the genome as intact gene sequences. Processed paralogs result in a distinct and under-appreciated source of conflict among gene trees because of RNA editing. Analyses with unidentified processed paralogs may yield incorrect phylogenies, and the sequences may evolve at different rates if the gene has been transferred from one genetic compartment (nuclear, mitochondrial, chloroplast) to another. Although RNA editing itself is not a problem in phylogenetic reconstruction, analyses should not combine mRNAs with DNAs, and processed paralogs should be either excluded or analyzed with caution.

Cyclooxygenase 2↗

PubMed2005

Minimal pre-mRNA substrates with natural and converted sites for full-round U insertion and U deletion RNA editing in trypanosomes.

Trypanosome RNA editing by uridylate insertion or deletion cycles is a mitochondrial mRNA maturation process catalyzed by multisubunit complexes. A full-round of editing entails three consecutive steps directed by partially complementary guide RNAs: pre-mRNA cleavage, U addition or removal, and ligation. The structural and functional composition of editing complexes is intensively studied, but their molecular interactions in and around editing sites are not completely understood. In this study, we performed a systematic analysis of distal RNA requirements for full-round insertion and deletion by purified editosomes. We define minimal substrates for efficient editing of A6 and CYb model transcripts, and established a new substrate, RPS12. Important differences were observed in the composition of substrates for insertion and deletion. Furthermore, we also showed for the first time that natural sites can be artificially converted in both directions: from deletion to insertion or from insertion to deletion. Our site conversions enabled a direct comparison of the two editing kinds at common sites during substrate minimization and demonstrate that all basic determinants directing the editosome to carry out full-round insertion or deletion reside within each editing site. Surprisingly, we were able to engineer a deletion site into CYb, which exclusively undergoes insertion in nature.

Adenosine Triphosphatases↗

PubMed2004

The 3'-untranslated region of cytochrome oxidase II mRNA functions in RNA editing of African trypanosomes exclusively as a cis guide RNA.

RNA editing in trypanosomes is a post-transcriptional process responsible for correcting the coding sequences of many mitochondrial mRNAs. Uridines are specifically added or deleted from mRNA by an enzymatic cascade in which a pre-edited mRNA is specifically cleaved, uridines are added or removed, and the corrected mRNA is ligated. The process is directed by RNA molecules, termed guide RNAs (gRNA). The ability of this class of small, noncoding RNA to function in RNA editing is essential for these organisms. Typically, gRNAs are transcribed independent of the their cognate mRNA and anneal to form a binary RNA complex . An exception for this process may be cytochrome oxidase subunit II (COII) mRNA since a gene encoding a trans acting gRNA has not been identified. Using an in vitro editing assay we find that the 3' UTR of COII, indeed, functions as a guide for both the site and number of uridines added to the coding region of the COII mRNA. We further show that the guiding sequence within the COII 3' UTR can only function in COII editing when contiguous with the editing substrate, indicating that the 3' UTR of COII lacks sequence or structure information necessary to function as a trans-acting gRNA. While other RNAs have been shown to "guide" RNA processing reactions, our discovery that the COII 3' UTR directs editing of its cognate mRNA in cis, is a unique function for a 3' UTR. The findings described here have led us to propose a new model for the evolution of gRNAs in kinetoplastids.

3' Untranslated Regions↗

PubMed1995

Guide RNA-mRNA chimeras, which are potential RNA editing intermediates, are formed by endonuclease and RNA ligase in a trypanosome mitochondrial extract.

RNA editing in kinetoplast mitochondrial transcripts involves the insertion and/or deletion of uridine residues and is directed by guide RNAs (gRNAs). It is thought to occur through a chimeric intermediate in which the 3' oligo(U) tail of the gRNA is covalently joined to the 3' portion of the mRNA at the site being edited. Chimeras have been proposed to be formed by a transesterification reaction but could also be formed by the known mitochondrial site-specific nuclease and RNA ligase. To distinguish between these models, we studied chimera formation in vitro directed by a trypanosome mitochondrial extract. This reaction was found to occur in two steps. First, the mRNA is cleaved in the 3' portion of the editing domain, and then the 3' fragment derived from this cleavage is ligated to the gRNA. The isolated mRNA 3' cleavage product is a more efficient substrate for chimera formation than is the intact mRNA, inconsistent with a transesterification mechanism but supporting a nuclease-ligase mechanism. Also, when normal mRNA cleavage is inhibited by the presence of a phosphorothioate, normal chimera formation no longer occurs. Rather, this phosphorothioate induces both cleavage and chimera formation at a novel site within the editing domain. Finally, levels of chimera-forming activity correlate with levels of mitochondrial RNA ligase activity when reactions are conducted under conditions which inhibit the ligase, including the lack of ATP containing a cleavable alpha-beta bond. These data show that chimera formation in the mitochondrial extract occurs by a nuclease-ligase mechanism rather than by transesterification.

Animals↗

PubMed2004

RNA editing in hepatitis delta virus: unsolved puzzles.

RNA editing, or post-transcriptional changes in the sequences of RNAs, is being increasingly recognized as an important player in the regulation of gene expression in vertebrates and invertebrates. Different types of RNA editing have been reported. This review discuss the type of RNA editing caused by cellular enzymes known as adenosine deaminases that act on RNAs (ADARs), and it"s significance in the lifecycle of an RNA virus, hepatitis delta virus.

Animals↗

PubMed1997

RNA editing in metazoan mitochondria: staying fit without sex.

RNA editing subsumes a number of functionally different mechanisms which have in common that they change the nucleotide sequence of RNA transcripts such that they become different from what would conventionally be predicted from their gene sequences. RNA editing has now been found in the organelles of numerous organisms as well as in a few nuclear transcripts. Most recently, it was shown to affect tRNAs in the mitochondria of several animals. The occurrence and evolutionary persistence of RNA editing is perplexing since backmutations in the genes might be assumed rapidly to eliminate the need for 'correction' of the gene sequences at the post-transcriptional level. Here, we review the recent RNA editing systems discovered in animal mitochondria and propose that they have arisen as a mechanism counteracting the accumulation of mutations that occurs in asexual genetic system.

Animals↗

PubMed1992

Formation of guide RNA/messenger RNA chimeric molecules in vitro, the initial step of RNA editing, is dependent on an anchor sequence.

Synthetic pre-edited messenger RNA (mRNA) and guide RNA (gRNA) for the 5'-edited maxicircle-encoded ND7 cryptogene from Leishmania tarentolae formed chimeric molecules upon incubation in the presence of a mitochondrial extract. These chimeric molecules consisted of the gRNAs covalently linked to the mRNAs by short oligo(U) tails at normal editing sites in most cases. Unlike the previously reported chimeras present in steady-state kinetoplast RNA, the in vitro-synthesized chimeras showed no editing of downstream editing sites. The synthesis of chimeric RNAs required ATP and was dependent on the formation of a gRNA/mRNA anchor duplex 3' of the pre-edited region, as shown by in vitro mutagenesis of the mRNA and the gRNA. mRNA sequences 3' and 5' of the pre-edited region also affected the efficiency of the chimera-forming activity. This in vitro system may accurately represent the initial step in RNA editing.

Animals↗

PubMed1992

Guide RNAs for transcripts with developmentally regulated RNA editing are present in both life cycle stages of Trypanosoma brucei.

RNA editing of several mitochondrial transcripts in Trypanosoma brucei is developmentally regulated. The cytochrome b and cytochrome oxidase II mRNAs are edited in procyclic-form parasites but are primarily unedited in bloodstream forms. The latter forms lack the mitochondrial respiratory system present in procyclic forms. Editing of the NADH dehydrogenase 7 (ND7) and ND8 transcripts is also developmentally regulated but occurs preferentially in bloodstream forms. Other transcripts, cytochrome oxidase III and ATPase 6, are edited in both life forms. We have identified many minicircle-encoded guide RNAs (gRNAs) for ATPase 6, ND7, and ND8. The characteristics of these gRNAs reveal how extensively edited RNA can be edited in the 3'-to-5' direction. Northern (RNA) blot and primer extension analyses indicate that gRNAs for transcripts whose editing is developmentally regulated are present in both procyclic and bloodstream form parasites. These results suggest that the developmental regulation of editing in these transcripts is not controlled by the presence or absence of gRNAs.

Aging↗

PubMed1993

RNA editing as a source of genetic variation.

Kinetoplastid RNA editing alters mitochondrial RNA transcripts by addition and deletion of uridine residues, producing open reading frames that may be twice as long as the original RNA. Although the COIII gene encoding cytochrome c oxidase subunit III in Trypanosoma brucei is edited along its entire length, the presumably homologous genes in two related trypanosomes, Leishmania tarentolae and Crithidia fasciculata, are only modestly edited at their 5' ends. We used a comparative approach to investigate the evolution of an edited gene and to determine how well editing creates conserved protein sequences. As RNA editing probably involves the pairing of several guide RNA molecules with the messenger RNA, we expected the edited proteins to be resistant to evolutionary change. Here we report that RNA editing is extensive in the mitochondria of four species of the insect parasite Herpetomonas, which is possibly an evolutionary precursor of T. brucei and L. tarentolae, and the discovery that RNA editing is a novel source of frameshift mutations over evolutionary time. The edited proteins accumulate mutations nearly twice as rapidly as the unedited versions.

Animals↗

PubMed2006

KISS: the kinetoplastid RNA editing sequence search tool.

Kinetoplastid mitochondrial mRNA editing is a post-transcriptional process of uridine insertion and deletion. Editing is mediated by small RNA molecules termed guide RNAs (gRNAs). Most gRNAs are encoded by numerous small circular DNA minicircles, while the protein coding mitochondrial genes are encoded on a separate, larger genome called the maxicircle. In order to provide a workbench for the analysis of RNA editing in kinetoplastids and a well-annotated set of guide RNAs for Trypanosoma brucei, we generated the kinetoplastid RNA editing sequence search tool (KISS) (http://gmod.mbl.edu/kiss/). KISS is a pipeline and database that uses BLAST comparisons and minicircle sequence motifs to annotate potential gRNAs and cognate mRNA editing sequence. KISS 1.0 contains all previously known minicircle and maxicircle data from Trypanosoma brucei plus >400 new minicircle sequences. Using an online format, KISS 1.0 allows the mapping and visualization of all known T. brucei gRNAs to minicircle genes and to potential mRNA substrates for RNA editing.

Animals↗

PubMed2006

The large form of ADAR 1 is responsible for enhanced hepatitis delta virus RNA editing in interferon-alpha-stimulated host cells.

Hepatitis delta virus (HDV) RNA editing controls the formation of hepatitis-delta-antigen-S and -L and therefore indirectly regulates HDV replication. Editing is thought to be catalysed by the adenosine deaminase acting on RNA1 (ADAR1) of which two different forms exist, interferon (IFN)-alpha-inducible ADAR1-L and constitutively expressed ADAR1-S. ADAR1-L is hypothesized to be a part of the innate cellular immune system, responsible for deaminating adenosines in viral dsRNAs. We examined the influence of both forms on HDV RNA editing in IFN-alpha-stimulated and unstimulated hepatoma cells. For gene silencing, an antisense oligodeoxyribonucleotide against a common sequence of both forms of ADAR1 and another one specific for ADAR1-L alone were used. IFN-alpha treatment of host cells led to approximately twofold increase of RNA editing compared with unstimulated controls. If ADAR1-L expression was inhibited, this substantial increase in editing could no longer be observed. In unstimulated cells, ADAR1-L suppression had only minor effects on editing. Inhibition of both forms of ADAR1 simultaneously led to a substantial decrease of edited RNA independently of IFN-alpha-stimulation. In conclusion, the two forms of ADAR1 are responsible almost alone for HDV editing. In unstimulated cells, ADAR1-S is the main editing activity. The increase of edited RNA under IFN-alpha-stimulation is because of induction of ADAR1-L, showing for the first time that this IFN-inducible protein is involved in the base modification of replicating HDV RNA. Thus, induction of ADAR1-L may at least partially cause the antiviral effect of IFN-alpha in natural immune response to HDV as well as in case of therapeutic administration of IFN.

Adenosine Deaminase↗

PubMed2004

Studying RNA editing in transgenic chloroplasts of higher plants.

RNA editing in plant cell organelles is a posttranscriptional process that changes the identity of individual nucleotides by pyrimidine transitions. C-to-U conversions are the predominantly found modifications in both mitochondrial and chloroplast transcripts of vascular plants. Research on functional, mechanistic, and evolutionary aspects of plant RNA editing has benefited immensely from the development of transgenic technologies for higher plant chloroplasts. This chapter describes methods for the generation of plants with stably transformed chloroplast genomes and their use for studying RNA editing processes in vivo.

Biolistics↗

PubMed1996

RNA editing in bryophytes and a molecular phylogeny of land plants.

RNA editing has been observed to date in all groups of vascular plants, but not in bryophytes. Its occurrence was therefore assumed to correlate with the evolution of tracheophytes. To gain more insight into both the phylogeny of early land plants and the evolution of mitochondrial RNA editing we have investigated a number of vascular and non-vascular plant species. Contrary to the belief that editing is absent from bryophytes, here we report mitochondrial RNA editing in cox3 mRNA of the liverwort Pellia epiphylla, the mosses Tetraphis pellucida and Ceratodon purpureus and the hornwort Anthroceros crispulus. RNA editing in plants consequently predates the evolution of tracheophytes. Editing is also found in the eusporangiate ferns Ophioglossum petiolatum and Angiopteris palmiformis, the whisk fern Tmesipteris elongata and the gnetopsid Ephedra gerardiana, but was not detected in Gnetum gnemon.cox3 mRNA of the lycopsid Isoetes lacustris shows the highest frequency of RNA editing ever observed in a plant, with 39% of all cytidine residues converted to uridines. The frequency of RNA editing correlates with the genomic GC content rather than with the phylogenetic position of a species. Phylogenetic trees derived from the slowly evolving mitochondrial sequences find external support from the assessments of classical systematics.

Base Sequence↗

PubMed2003

RNA editing in hornwort chloroplasts makes more than half the genes functional.

RNA editing in chloroplasts alters the RNA sequence by converting C-to-U or U-to-C at a specific site. During the study of the complete nucleotide sequence of the chloroplast genome from the hornwort Anthoceros formosae, RNA editing events have been systematically investigated. A total of 509 C-to-U and 433 U-to-C conversions are identified in the transcripts of 68 genes and eight ORFs. No RNA editing is seen in any of the rRNA but one tRNA suffered a C-to-U conversion at an anticodon. All nonsense codons in 52 protein-coding genes and seven ORFs are removed in the transcripts by U-to-C conversions, and five initiation and three termination codons are created by C-to-U conversions. RNA editing in intron sequence suggests that editing can precede intercistronic processing. The sequence complementary to the edited site is proposed as a distant cis-recognition element.

Amino Acid Substitution↗

PubMed1995

RNA editing in higher plant mitochondria: analysis of biochemistry and specificity.

RNA editing alters genomically encoded cytidines to uridines posttranscriptionally in higher plant mitochondria. Most of these editing events occur in translated regions and consequently alter the amino acid sequence. In Oenothera berteriana more than 500 editing sites have been detected and the total number of editing sites exceeds 1000 sites in this mitochondrial genome. To identify the components involved in this process we investigated the factors determining the specificity of RNA editing and the apparent conversion of cytidine to uridine residues. The possible biochemical reactions responsible for RNA editing in plant mitochondria are de- or transamination, base substitution and nucleotide replacement. In order to discriminate between these different biochemical mechanisms we followed the fate of the sugar-phosphate backbone by analysing radiolabeled nucleotides after incorporation into high molecular mass RNA. Plant mitochondria were supplied with [alpha-32P]CTP to radiolabel CMP residues in newly synthesized transcripts. Radiolabeled mtRNA was extracted and digested with nuclease P1 to hydrolyse the RNA to monophosphates. The resulting monophosphates were analysed on one- and two-dimensional TLC systems to separate pC from pU. Radiolabeled pU was detected in increasing quantities during the course of incubation. These results suggest that RNA editing in plant mitochondria involves either a deamination or a transglycosylation reaction. The editing product was identified as uridine and not as a hypermodified nucleotide which is recognized as uridine. Similar results have been obtained by incubating in vitro transcribed mRNAs with mitochondrial lysates indicating that RNA editing and transcription is not directly linked in plant mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Evolution↗