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PubMed2006

EdiPy: a resource to simulate the evolution of plant mitochondrial genes under the RNA editing.

EdiPy is an online resource appropriately designed to simulate the evolution of plant mitochondrial genes in a biologically realistic fashion. EdiPy takes into account the presence of sites subjected to RNA editing and provides multiple artificial alignments corresponding to both genomic and cDNA sequences. Each artificial data set can successively be submitted to main and widespread evolutionary and phylogenetic software packages such as PAUP, Phyml, PAML and Phylip. As an online bioinformatic resource, EdiPy is available at the following web page: http://biologia.unical.it/py_script/index.html.

Computational Biology↗

PubMed1996

Preferential RNA editing at specific sites within transcripts of two plant mitochondrial genes does not depend on transcriptional context or nuclear genotype.

Transcripts of most plant mitochondrial protein-coding genes exhibit C-to-U RNA editing events. In Petunia, two co-transcribed genes, nad3 and rps12, exhibit transcripts which are not fully edited at all potential editing sites. We investigated the nad3/rps12 transcript population in four different genotypes. In one pair of genotypes, the nuclear genome is identical but the nad3/rps12 genes are in different transcriptional contexts. Both the nad3/ rps12 genes and the plant mitochondrial genomes are identical in a second pair of genotypes, but the nuclear background is derived from two different Petunia species. We found that the overall extent of editing varied greatly between genotypes and is affected by nuclear genotype but not by the global transcriptional context. Local sequence context around a particular site does affect editing frequency. In all genotypes, certain sites exhibit high editing frequency, but these sites do not share obvious primary sequence characteristics. In all genotypes examined, editing sites which do not affect the encoded amino acid are less frequently edited than sites which alter codons to non-synonymous forms. All these data indicate that an unidentified property of the sequences immediately surrounding a cytosine affect its selection as a target in the editing process.

Amino Acid Sequence↗

PubMed2006

In Trypanosoma brucei RNA editing, TbMP18 (band VII) is critical for editosome integrity and for both insertional and deletional cleavages.

In trypanosome RNA editing, uridylate (U) residues are inserted and deleted at numerous sites within mitochondrial pre-mRNAs by an approximately 20S protein complex that catalyzes cycles of cleavage, U addition/U removal, and ligation. We used RNA interference to deplete TbMP18 (band VII), the last unexamined major protein of our purified editing complex, showing it is essential. TbMP18 is critical for the U-deletional and U-insertional cleavages and for integrity of the approximately 20S editing complex, whose other major components, TbMP99, TbMP81, TbMP63, TbMP52, TbMP48, TbMP42 (bands I through VI), and TbMP57, instead sediment as approximately 10S associations. Additionally, TbMP18 augments editing substrate recognition by the TbMP57 terminal U transferase, possibly aiding the recognition component, TbMP81. The other editing activities and their coordination in precleaved editing remain active in the absence of TbMP18. These data are reminiscent of the data on editing subcomplexes reported by A. Schnaufer et al. (Mol. Cell 12:307-319, 2003) and suggest that these subcomplexes are held together in the approximately 20S complex by TbMP18, as was proposed previously. Our data additionally imply that the proteins are less long-lived in these subcomplexes than they are when held in the complete editing complex. The editing endonucleolytic cleavages being lost when the editing complex becomes fragmented, as upon TbMP18 depletion, should be advantageous to the trypanosome, minimizing broken mRNAs.

Animals↗

PubMed1997

RNA editing and hypermutation by adenosine deamination.

Double-stranded RNA adenosine deaminase (dsRAD) was discovered ten years ago. In the intervening decade, research on dsRAD has progressed not only predictably, such as with the purification of the enzyme and identification of cDNAs, but also in some quite surprising ways. This review covers both areas of progress, but will concentrate on the surprises, which include the discovery that dsRAD is a member of a larger family of deaminases and the identification of RNAs that appear to be targets for these deaminases in vivo.

Adenosine Deaminase↗

PubMed1997

RNA editing status of nad7 intron domains in wheat mitochondria.

The most highly conserved structures of group II introns are the helical domains V and VI near the 3'splice site. Within this region of each of the four introns in the wheat mitochondrial nad7 gene encoding NADH dehydrogenase subunit 7, there are A-C mispairs. To determine whether C-to-U type RNA editing restores conventional A-U pairing, we sequenced RT-PCR products from partially-spliced nad7 template RNA and gel-fractionated, excised intron RNA. We examined transcripts from germinating wheat embryos and seedlings because these two stages of development show pronounced differences in steady state levels of nad7 intronic RNAs. We observed editing at only two of the six predicted sites, and they were located at homologous positions within domain V of the third and fourth introns. A third site was found to be edited within the unmodelled domain VI loop of the fourth intron. Similar patterns of RNA editing were seen in wheat embryos and seedlings. These observations, and the presence of other non-conventional base pairs particularly within domain V of plant mitochondrial introns, indicate weaker helical core structure than in ribozymic group II introns. Moreover, the incompleteness or absence of editing in wheat nad7 excised intron RNA suggests that, although editing may contribute to splicing efficiency, it is not essential for splicing.

Base Composition↗

PubMed1993

RNA editing in mitochondria of Leishmania tarentolae and Crithidia fasciculata.

The uridine sequence of mitochondrial pre-mRNAs in trypanosomes is post-transcriptionally altered by an RNA editing process, the information for which is provided by small guide (g)RNAs. Current editing models are based on the occurrence in mitochondrial RNA of chimeric molecules in which a gRNA is covalently linked to an editing site through its 3' end. This review describes some of the work done in Leishmania tarentolae that led to the construction of these models, in comparison to data obtained in Crithidia fasciculata. In spite of the virtually complete conservation of editing patterns and genomic organization between the two species, the properties of gRNAs and chimeric molecules in C. fasciculata put the editing models in a slightly different perspective.

Animals↗

PubMed1994

RNA editing in trypanosomes.

The nucleotide sequence of mitochondrial pre-mRNAs in trypanosomes is posttranscriptionally edited by the insertion and deletion of uridylate (U) residues. In some RNAs editing is limited to small sections but in African trypanosomes, such as Trypanosoma brucei, 9 of the 18 known mitochondrial mRNAs are created by massive editing which can produce more than 50% of the coding sequence. In all cases, however, RNA editing is a key event in gene expression during which translatable RNAs are generated. The information for the editing process and possibly also the inserted Us are provided by small guide RNAs, which are encoded in both the maxicircle and minicircle components of the trypanosome mitochondrial DNA. Current models of editing are largely based on the characteristics of partially edited RNAs and on the occurrence in vivo and the possibility of synthesis in vitro of chimeric molecules in which a guide RNA is covalently linked through its 3' oligo(U) tail to an editing site in pre-mRNA. In this paper, I will review the research in this rapidly growing field and illustrate how different interpretations of the available data can lead to different views of the mechanism and the biochemistry of the editing process.

Animals↗

PubMed1993

RNA editing of AMPA receptor subunit GluR-B: a base-paired intron-exon structure determines position and efficiency.

A functionally critical position (Q/R site) of the AMPA receptor subunit GluR-B is controlled by RNA editing that operates in the nucleus, since in brain and clonal cell lines of neural origin, unspliced GluR-B transcripts occur edited in the Q/R site CAG codon and, additionally, in intronic adenosines. Transfection of GluR-B gene constructs into PC12 cells revealed that the proximal part of the intron downstream of the unedited exonic site is required for Q/R site editing. This intron portion contains an imperfect inverted repeat preceding a 10 nt sequence with exact complementarity to the exon centered on the unedited codon. Single nucleotide substitutions in this short intronic sequence or its exonic complement curtailed Q/R site editing, which was recovered by restoring complementarity in the respective partner strand. Base conversion in the channel-coding region of GluR-B directed by base paired sequences may be executed by a ubiquitous nuclear adenosine deaminase specific for double-stranded RNA.

Adenosine Deaminase↗

PubMed2002

TbMP81 is required for RNA editing in Trypanosoma brucei.

Most mitochondrial mRNAs are edited in Trypano soma brucei by a series of steps that are catalyzed by a multienzyme complex that is in its initial stages of characterization. RNA interference (RNAi)-mediated repression of the expression of TbMP81, a zinc finger protein component of the complex, inhibited growth of bloodstream and insect forms, and blocked in vivo RNA editing. This repression preferentially inhibited insertion editing compared with deletion editing in vitro. It resulted in reduced specific endoribonucleolytic cleavage and a greater reduction of U addition and associated RNA ligation activities than U removal and associated RNA ligation activities. The repressed cells retained 20S editing complexes with several demonstrable proteins and adenylatable TbMP52 RNA ligase, but adenlyatable TbMP48 was not detected. Elimination of TbMP48 by RNAi repression did not inhibit cell growth or in vivo editing in either bloodstream or procyclic forms. These results indicate that TbMP81 is required for RNA editing and suggest that the editing complex is functionally partitioned.

Animals↗

PubMed2000

RNA editing of the human serotonin 5-HT(2C) receptor delays agonist-stimulated calcium release.

RNA encoding the human 5-HT(2C) receptor undergoes adenosine-to-inosine RNA editing events at five positions in the putative second intracellular loop, with a corresponding reduction in receptor/G-protein coupling. Agonist-stimulated calcium release was examined in NIH-3T3 fibroblasts stably expressing the nonedited human INI (hINI) or the edited hVSV or hVGV variants. We hypothesized that different receptor isoforms would show altered dynamics of agonist-induced calcium release. The three isoforms showed a rightward shift in agonist concentration-response curves for eliciting calcium release (EC(50) values: hINI, 2.2 nM; hVSV, 15 nM; hVGV, 49 nM). Additionally, the hVGV receptor showed a blunted and delayed [Ca(2+)](i) peak compared with the hINI or hVSV receptor isoforms. These distinctions in agonist-induced [Ca(2+)](i) release imply that edited 5-HT(2C) receptors may produce distinct physiological responses within the central nervous system.

3T3 Cells↗

PubMed1997

Reduced requirement for RNA editing in the mitochondrial cox3 transcript of Olea europaea L.

Transcripts from the mitochondrial cox3 locus in Olea europaea L. are edited in ten nucleotide positions. Nine of these C-to-U transitions affect 3.4% of the genomically encoded amino-acid identity to specify a COXIII polypeptide better conserved in evolution. RNA editing of cox3 in olive tree mitochondria is, thus, less extensive than in the other higher plants so far investigated. This low RNA editing frequency might correlate with both the GC content observed in the cox3 gene and the phylogenetic position of Olea.

Amino Acid Sequence↗

PubMed2002

RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans.

Here we take advantage of the well-characterized and simple nervous system of Caenorhabditis elegans to further our understanding of the functions of RNA editing. We describe the two C.elegans ADAR genes, adr-1 and adr-2, and characterize strains containing homozygous deletions in each, or both, of these genes. We find that adr-1 is expressed in most, if not all, cells of the C.elegans nervous system and also in the developing vulva. Using chemotaxis assays, we show that both ADARs are important for normal behavior. Biochemical, molecular and phenotypic analyses indicate that ADR-1 and ADR-2 have distinct roles in C.elegans, but sometimes act together.

Adenosine Deaminase↗

PubMed1997

The centrosomal protein centrosomin A and the nuclear protein centrosomin B derive from one gene by post-transcriptional processes involving RNA editing.

The identification of a gene encoding concomitantly a nuclear protein and an intrinsic centrosomal protein further emphasizes the close and presumably developmental relationship between the cell nucleus and the centrosome. Screening of a murine RNA-based cDNA library with an antiserum to a centrosomal protein and rescreening with the insert of an initial clone released two complete cDNAs (1.2 kbp and 2.2 kpb) coding for proteins with notable characteristics. The amino-terminal sections of centrosomin A (276 amino acid residues, molecular mass 34.5 kDa) and of centrosomin B (447 amino acid residues, molecular mass 54.8 kDa) are identical over 272 amino acid residues. The carboxy-terminal section of the larger protein comprises additional 175 amino acid residues including nuclear location signals. The mRNAs encoding centrosomin A and B derive from a single gene. Chromogenomic DNA as template and primer pairs complementary to the sequence which is identical in centrosomin A and B cDNAs results in amplification of only one DNA fragment. Moreover, one exon of the genomic sequence and the centrosomin B-encoding cDNA sequence include a G which is deleted in the centrosomin A-encoding cDNA. Accordingly, the two mRNAs are the products of either alternative splicing or alternative polyadenylation in combination with RNA editing. The recombinantly expressed chimeric protein consisting of centrosomin A and the green fluorescent protein from Aequorea victoria accumulates in centrosomes while the corresponding fusion protein with the centrosomin B sequence is transported into nuclei.

Amino Acid Sequence↗

PubMed1998

5' end maturation and RNA editing have to precede tRNA 3' processing in plant mitochondria.

We report the characterization and partial purification of potato mitochondrial RNase Z, an endonuclease that generates mature tRNA 3' ends. The enzyme consists of one (or more) protein(s) without RNA subunits. Products of the processing reaction are tRNA molecules with 3' terminal hydroxyl groups and 3' trailers with 5' terminal phosphates. The main processing sites are located immediately 3' to the discriminator and one nucleotide further downstream. This endonucleolytic processing at and close to the tRNA 3' end in potato mitochondria suggests a higher similarity to the eukaryotic than to the prokaryotic tRNA 3' processing pathway. Partial purification and separation of RNase Z from the 5' processing activity RNase P allowed us to determine biochemical characteristics of the enzyme. The activity is stable over broad pH and temperature ranges, with peak activity at pH 8 and 30 degrees C. Optimal concentrations for MgCl2 and KCl are 5 mM and 30 mM, respectively. The potato mitochondrial RNase Z accepts only tRNA precursors with mature 5' ends. The precursor for tRNAPhe requires RNA editing for efficient processing by RNase Z.

Base Sequence↗

PubMed2006

Algorithmic approaches for identification of RNA editing sites.

Recently a number of groups have introduced computational methods for the detection of A-to-I RNA editing sites. These approaches have resulted in finding thousands of editing sites within the genomic repeats, as well as a few novel genetic recoding sites. We review these recent advancements, emphasizing the principles underlying the various methods used. Possible directions for extending these methods are discussed.

Algorithms↗

PubMed1999

Familial hypercholesterolemia. Acceptor splice site (G-->C) mutation in intron 7 of the LDL-R gene: alternate RNA editing causes exon 8 skipping or a premature stop codon in exon 8. LDL-R(Honduras-1) [LDL-R1061(-1) G-->C].

Familial hypercholesterolemia (FH) is an autosomal dominant lipoprotein disorder caused by defects in the low density lipoprotein (LDL) receptor (R) gene. We report a novel mutation of the LDL-R gene in a 38-year-old man with homozygous FH from the province of Trujilo in Northern Honduras. The patient presented with tendinous xanthomas over the extensor tendons as well as xanthelasmas at sites of surgical scars. He was diagnosed with severe coronary artery disease requiring revascularization at age 29. After an unsuccessful course of treatment with simvastatin, the patient has been treated with plasma apheresis and macromolecular plasma filtration bi-monthly. Haplotyping of the LDL-R gene revealed homozygosity for the rare 'J' allele and a loss of the EcoRV restriction cleavage site in exon 8. Single stranded conformational polymorphism of exons 3, 6, 7, 9, 10 and 8 reveals an abnormal migration pattern in exon 8. Direct sequencing of the promoter region, exons 1, 4, 8 and 13 revealed two RFLP's and a novel mutation in intron 7. This mutation consists of G-->C transposition at the acceptor splice site of exon 8 at the last nucleotide of intron 7 [LDL-R1061(-1)G-->C]. Reverse transcriptase (RT) PCR amplification of RNA from monocytes obtained from the patient reveals a decrease in LDL-R mRNA (52% of control) and skipping of exon 8 (approximately 38%, as assessed by densitometric scanning of the amplified fragments) to form a new RNA transcript that includes exons 7 and 9 without frameshift. Alternative RNA editing leads to a new cryptic acceptor splice site 17 bp downstream in exon 8 producing a frameshift mutation and a predicted premature stop codon 1138 bp from the transcriptional start site (approxiamtely 62%). Western blotting analysis using a monoclonal antibody (C7) directed at the amino terminus of the LDL-R protein reveals a marked reduction in LDL-R protein expressed in monocytes obtained from the patient. We conclude that LDL-R1061(-1)G-->C is a novel mutation of the LDL-R gene that results in marked decrease in LDL-R mRNA levels and protein expression by two alternate RNA editing mechanisms, that cause skipping of exon 8 or the use of a novel cryptic acceptor splice site in exon 8 with a frameshift and premature stop codon. The patient continues to do well on selective plasma filtration but developed bilateral severe carotid artery disease requiring surgical intervention.

Adult↗

PubMed1998

Analysis of RNA editing in plastids.

Chloroplast mRNAs can be subject to posttranscriptional pyrimidine-to-pyrimidine conversions at highly specific sites. This RNA modification mechanism shows a high degree of similarity to plant mitochondrial editing but differs markedly from, and is most likely evolutionarily unrelated to, all other RNA editing systems. The study of RNA editing processes in chloroplasts has been largely hampered by the lack of in vitro editing systems; however, considerable insights into the recognition mechanisms of individual editing sites have come from in vivo approaches. Chloroplast transformation proved to be a particularly useful tool to study plastid RNA editing. In this article, specific methods for the analysis of chloroplast RNA editing are discussed. Detailed experimental procedures are provided for (i) the purification of chloroplasts and (ii) the stable genetic transformation of higher plant plastids.

Chloroplasts↗

PubMed2004

Complex cis-elements determine an RNA editing site in pea mitochondria.

The cis-requirements for the first editing site in the atp9 mRNA from pea mitochondria were investigated in an in vitro RNA editing system. Template RNAs deleted 5' of -20 are edited correctly, but with decreased efficiency. Deletions between -20 and the edited nucleotide abolish editing activity. Substitution of the sequences 3' of the editing site has little effect, which suggests that the major determinants reside upstream. Stepwise mutated RNA sequences were used as templates or competitors that divide the cis-elements into several distinct regions. In the template RNAs, mutation of the sequence between -40 and -35 reduces the editing activity, while the region from -15 to -5 is essential for the editing reaction. In competition experiments the upstream region can be titrated, while the essential sequence near the editing site is largely resistant to excess competitor. This observation suggests that either one trans-factor attaches to these separate cis-regions with different affinities or two distinct trans-factors bind to these sequences, and one of which is present in limited amounts, whereas the other one is more abundant in the lysate.

Arabidopsis Proteins↗