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PubMed2002

Chloroplast ribosomal S14 protein transcript is edited to create a translation initiation codon in the moss Physcomitrella patens.

The rps14 transcript is edited in the moss Physcomitrella patens chloroplast by a C-to-U transition, to create a translation initiation codon, AUG. The efficiency of RNA editing was low, with approximately 20% of rps14 transcripts edited. This suggests that the translation of rps14 mRNA is strictly regulated by RNA editing. This is the first report of RNA editing in P. patens and the creation of a translation initiation codon in rps14 mRNA in chloroplasts.

Amino Acid Sequence↗

PubMed2005

Q/R site editing controls kainate receptor inhibition by membrane fatty acids.

RNA editing within the pore loop controls the pharmacology and permeation properties of ion channels formed by neuronal AMPA and kainate receptor subunits. Genomic sequences for the glutamate receptor 2 (GluR2) subunit of AMPA receptors and the GluR5 and GluR6 subunits of kainate receptors all encode a neutral glutamine (Q) residue within the channel pore that can be converted by RNA editing to a positively charged arginine (R). Receptors comprised of unedited subunits are permeable to calcium and display inwardly rectifying current-voltage relationships, because of blocking of outward current by intracellular polyamines. In contrast, receptors that include edited subunits conduct less calcium, resist polyamine block, and have relatively linear current-voltage relationships. We showed previously that cis-unsaturated fatty acids, including arachidonic acid and docosahexanoic acid, exert a potent block of native kainate receptors as well as homomeric recombinant receptors formed by transfection of heterologous cells with cDNA for the GluR6(R) subunit. Here, we show that fatty acid blockade of recombinant homomeric and heteromeric kainate receptors is strongly dependent on editing at the Q/R site. Recombinant channels that include unedited subunits exhibit significantly weaker block than channels made up of fully edited subunits. Inhibition of fully edited channels is equivalent at voltages from -70 to +40 mV and is noncompetitive, consistent with allosteric regulation of channel function.

Animals↗

PubMed2003

A tale of two TUTases.

The insertion and deletion of U residues at specific sites in mRNAs in trypanosome mitochondria is thought to involve 3' terminal uridylyl transferase (TUTase) activity. TUTase activity is also required to create the nonencoded 3' oligo[U] tails of the transacting guide RNAs (gRNAs). We have described two TUTases, RET1 (RNA editing TUTase 1) and RET2 (RNA editing TUTase 2) as components of different editing complexes. Tandem affinity purification-tagged Trypanosoma brucei RET2 (TbRET2) was expressed and localized to the cytosol in Leishmania tarentolae cells by removing the mitochondrial signal sequence. Double-affinity isolation yielded tagged TbRET2, together with a few additional proteins. This material exhibits a U-specific transferase activity in which a single U is added to the 3' end of a single-stranded RNA, thereby confirming that RET2 is a 3' TUTase. We also found that RNA interference of RET2 expression in T. brucei inhibits in vitro U-insertion editing and has no effect on the length of the 3' oligo[U] tails of the gRNAs, whereas down-regulation of RET1 has a minor effect on in vitro U-insertion editing, but produces a decrease in the average length of the oligo[U] tails. This finding suggests that RET2 is responsible for U-insertions at editing sites and RET1 is involved in gRNA 3' end maturation, which is essential for creating functional gRNAs. From these results we have functionally relabeled the previously described TUT-II complex containing RET1 as the guide RNA processing complex.

Animals↗

PubMed1994

Alternative polyadenylation of apolipoprotein B RNA is a major cause of B-48 protein formation in rat hepatoma cell lines transfected with human apoB-100 minigenes.

The human apoB gene encodes an mRNA of 14121 nucleotides. In liver the apoB gene products a full-length mature protein of 4,536 amino acids (B-100), whereas in the intestine this gene produces a truncated protein of 2,152 amino acids (B-48). B-48 results from RNA editing of nucleotide 6666 from C to U, thereby producing a stop codon at position 2153. Rat liver has been shown to contain apoB RNA editing capability resulting in production of both B-100 and B-48. To create an in vitro expression system for human B-100, a minigene with a wild type coding sequence for the entire B-100 protein (B-100/Gln) was stably transfected into rat hepatoma cells (McA-RH7777). Similarly, a minigene with mutation at nucleotide 6667 that allowed translation even after editing of nucleotide 6666 (B-100/Leu, nonstop mutant), a minigene with an additional nonsense mutation at nucleotide 7053 to produce B-50 (B-50/Leu), and a truncated wild type minigene with a stop signal at codon 3261 to produce B-74 and an mRNA of 10 kb (B-74/Gln) were also transfected. Very little full-length B-100 and B-74 was produced by any of the respective constructions, including the B-100/Leu with the nonstop mutation. Transfection with B-100/Gln, B-100/Leu and B-74/Gln constructions produced greater than 90% of apoB as B-48, whereas the B-50/Leu construction produced 76% B-50 and 24% B-48. The inability of the B-100/Leu construction to produce B-100 suggested an explanation for B-48 production other than RNA editing. Northern blot analysis showed that the RNA produced by all four transfectants was shortened to a size of about 7 kb. A 10-kb but no 7-kb RNA was observed in the B-74/Leu construction when transfected to Chinese hamster ovary cells suggesting cell type specificity in generation of a shortened RNA. The 3' end of apoB RNA from McA-RH7777 B-100/Leu transfectants was reverse transcribed, cloned, and sequenced. This revealed two species of RNA: one polyadenylated at or near nucleotide 6775 capable of coding for B-48, the other polyadenylated at nucleotide 7080 capable of coding for B-50. In 18% of the cDNA clones, nucleotide 6666 was edited from C to T. In 6 of 34 clones, addition of the poly(A) tail after nucleotide 6774 created a TAA stop codon, whereas no stop signals could be detected in the remaining clones.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2005

Pigment deficiency in nightshade/tobacco cybrids is caused by the failure to edit the plastid ATPase alpha-subunit mRNA.

The subgenomes of the plant cell, the nuclear genome, the plastome, and the chondriome are known to interact through various types of coevolving macromolecules. The combination of the organellar genome from one species with the nuclear genome of another species often leads to plants with deleterious phenotypes, demonstrating that plant subgenomes coevolve. The molecular mechanisms behind this nuclear-organellar incompatibility have been elusive, even though the phenomenon is widespread and has been known for >70 years. Here, we show by direct and reverse genetic approaches that the albino phenotype of a flowering plant with the nuclear genome of Atropa belladonna (deadly nightshade) and the plastome of Nicotiana tabacum (tobacco) develops as a result of a defect in RNA editing of a tobacco-specific editing site in the plastid ATPase alpha-subunit transcript. A plastome-wide analysis of RNA editing in these cytoplasmic hybrids and in plants with a tobacco nucleus and nightshade chloroplasts revealed additional defects in the editing of species-specific editing sites, suggesting that differences in RNA editing patterns in general contribute to the pigment deficiencies observed in interspecific nuclear-plastidial incompatibilities.

Atropa belladonna↗

PubMed1999

Editing of messenger RNA precursors and of tRNAs by adenosine to inosine conversion.

The double-stranded RNA-specific adenosine deaminases ADAR1 and ADAR2 convert adenosine (A) residues to inosine (I) in messenger RNA precursors (pre-mRNA). Their main physiological substrates are pre-mRNAs encoding subunits of ionotropic glutamate receptors or serotonin receptors in the brain. ADAR1 and ADAR2 have similar sequence features, including double-stranded RNA binding domains (dsRBDs) and a deaminase domain. The tRNA-specific adenosine deaminases Tad1p and Tad2p/Tad3p modify A 37 in tRNA-Ala1 of eukaryotes and the first nucleotide of the anticodon (A 34) of several bacterial and eukaryotic tRNAs, respectively. Tad1p is related to ADAR1 and ADAR2 throughout its sequence but lacks dsRBDs. Tad1p could be the ancestor of ADAR1 and ADAR2. The deaminase domains of ADAR1, ADAR2 and Tad1p are very similar and resemble the active site domains of cytosine/cytidine deaminases.

Adenosine↗

PubMed2002

DNA double-strand breaks: prior to but not sufficient in targeting hypermutation.

The activation-induced cytidine deaminase (AID) is required for somatic hypermutation (SHM) and class-switch recombination (CSR) of immunoglobulin (Ig) genes, both of which are associated with DNA double-strand breaks (DSBs). As AID is capable of deaminating deoxy-cytidine (dC) to deoxy-uracil (dU), it might induce nicks (single strand DNA breaks) and also DNA DSBs via a U-DNA glycosylase-mediated base excision repair pathway ('DNA-substrate model'). Alternatively, AID functions like its closest homologue Apobec1 as a catalytic subunit of a RNA editing holoenzyme ('RNA-substrate model'). Although rearranged Vlambda genes are preferred targets of SHM we found that germinal center (GC) B cells of AID-proficient and -deficient Vlambda1-expressing GC B cells display a similar frequency, distribution, and sequence preference of DSBs in rearranged and also in germline Vlambda1 genes. The possible roles of DSBs in relation to AID function and SHM are discussed.

Animals↗

PubMed1994

The formation of mitochondrial ribonucleoprotein complexes involving guide RNA molecules in Trypanosoma brucei.

Transcripts from mitochondrial (maxicircle) genes of kinetoplastid organisms undergo RNA editing characterized by a series of reactions that insert and delete uridine nucleotides within the sequence of the pre-mRNAs. Guide RNAs, which complement fully edited mRNAs, provide the information for the edited sequence by an unknown mechanism. We report here that guide RNA molecules associate with other mitochondrial components to form four specific, stable ribonucleoprotein complexes. The complexes form very rapidly at a low monovalent cation concentration, and their formation is blocked by heparin or pretreatment of the mitochondrial lysate with SDS. ATP hydrolysis is not required but slightly stimulates complex association up to concentrations of 5 mM. The results are suggestive of a sequential assembly of the ribonucleoprotein complexes, and their possible involvement during the kinetoplastid RNA editing is discussed.

Amino Acid Sequence↗

PubMed2002

Two novel transcripts for human endothelin B receptor produced by RNA editing/alternative splicing from a single gene.

Hirschsprung disease is a heterogeneous genetic disorder, causative genes of which include the endothelin B receptor (ETB). To investigate the mutations of ETB in Hirschsprung disease, expression of the ETB gene in lymphoblastoid cells from patients and normal healthy adults was examined, and novel mutant transcripts were found. The mutant ETB gene transcripts lacked a 134-bp nucleotide sequence corresponding to exon 5, and some also contained a substitution from A to G at position 950 in exon 4, resulting in an amino acid substitution from glutamine (Q) to arginine (R). This substitution was suspected to be the result of RNA editing because it was not present in the genomic sequence. Transfection experiments using ETB minigenes containing the editing site with or without the gene for double-strand RNA deaminases (ADAR1 and ADAR2) revealed that the deaminases were involved in RNA editing. Furthermore, a c-Myc-tagged mutant ETB protein was not detected by Western blot analysis. The present results show that the mutant ETB transcripts were novel splice variants, which might not be translated, or that the products translated from splice variants might be quickly degraded, presumably because of their instability. The preferential production of this null function ETB by RNA editing/splicing could be involved in the etiology of some cases of Hirschsprung disease.

Alleles↗

PubMed2005

Editing of the grapevine mitochondrial cytochrome b mRNA and molecular modeling of the protein.

Cytochrome b (COB), the central catalytic subunit of ubiquinol cytochrome c reductase, is a component of the transmembrane electron transfer chain that generates proton motive force. Some plant COB mRNAs are processed by RNA editing, which changes the gene coding sequence. This report presents the sequences of the grapevine (Vitis vinifera L.) mitochondrial gene for apocytochrome b (cob), the edited mRNA and the deduced protein. Grapevine COB is 393 amino acids long and is 98% identical to homologs in rapeseed, Arabidopsis thaliana and Oenothera sp. Twenty-one C-U editing sites were identified in the grapevine cob mRNA, resulting in 20 amino acid changes. These changes increase the overall hydrophobicity of the protein and result in a more conserved protein. Molecular modeling of grapevine COB shows that residues changed by RNA editing fit the secondary structure characteristic of an integral membrane protein. This is the first complete mitochondrial gene reported for grapevine. Novel RNA editing sites were identified in grapevine cob, which have not been previously reported for other plants.

Amino Acid Sequence↗

PubMed2006

Sequence of the tomato chloroplast DNA and evolutionary comparison of solanaceous plastid genomes.

Tomato, Solanum lycopersicum (formerly Lycopersicon esculentum), has long been one of the classical model species of plant genetics. More recently, solanaceous species have become a model of evolutionary genomics, with several EST projects and a tomato genome project having been initiated. As a first contribution toward deciphering the genetic information of tomato, we present here the complete sequence of the tomato chloroplast genome (plastome). The size of this circular genome is 155,461 base pairs (bp), with an average AT content of 62.14%. It contains 114 genes and conserved open reading frames (ycfs). Comparison with the previously sequenced plastid DNAs of Nicotiana tabacum and Atropa belladonna reveals patterns of plastid genome evolution in the Solanaceae family and identifies varying degrees of conservation of individual plastid genes. In addition, we discovered several new sites of RNA editing by cytidine-to-uridine conversion. A detailed comparison of editing patterns in the three solanaceous species highlights the dynamics of RNA editing site evolution in chloroplasts. To assess the level of intraspecific plastome variation in tomato, the plastome of a second tomato cultivar was sequenced. Comparison of the two genotypes (IPA-6, bred in South America, and Ailsa Craig, bred in Europe) revealed no nucleotide differences, suggesting that the plastomes of modern tomato cultivars display very little, if any, sequence variation.

Amino Acid Sequence↗

PubMed1991

Multiple trans-splicing events are required to produce a mature nad1 transcript in a plant mitochondrion.

The mitochondrial gene encoding NADH dehydrogenase subunit 1 (nad1) in Petunia hybrida is split into five exons, a, b, c, d, and e. With the use of a complete restriction map of the 443-kb Petunia mitochondrial genome, we have cloned these exons and mapped their location. Exon a is located 130 kb away from and in the opposite orientation from exons b and c. Exon d maps 95 kb away and in the opposite orientation from exons b and c. Exons d and e are separated by 190 kb. By performing the polymerase chain reaction on Petunia cDNAs, we have shown that transcripts from these five exons are joined via a series of cis- and trans-splicing events to create a mature nad1 transcript. In addition, we have found 23 C----U RNA edit sites in Petunia nad1. RNA editing changes 19 of the amino acids predicted by the genomic sequence.

Amino Acid Sequence↗

PubMed1999

Diversification of Drosophila chloride channel gene by multiple posttranscriptional mRNA modifications.

We have identified and analyzed a Drosophila melanogaster gene that encodes a chloride channel subunit (DrosGluCl-alpha) previously shown to function as a glutamate-gated chloride channel in an in vitro expression system. Sequence analysis of several cDNAs corresponding to the gene revealed sequence diversity in their open reading frames at seven specific sites. Site-specific A-to-G variations between cDNA and genomic sequences, consistent with RNA editing, were detected at five nucleotide positions. In addition, sequence variations among cDNA clones consistent with alternative splicing of mRNA were found at two different sites. In the 5' region, two small adjacent exons, containing similar but distinct modular sequences, are alternatively incorporated into the mature mRNA. In the 3' region, alternative splicing generates a variant encoding a protein with four additional amino acids just upstream of the fourth transmembrane domain. Combinations of RNA editing and alternative splicing can lead to extensive diversification of transcripts. These results give the first example of RNA editing in neurotransmitter-gated chloride channel genes or of alternative splicing in a glutamate-gated chloride channel gene of Drosophila.

Alternative Splicing↗

PubMed1988

Editing of kinetoplastid mitochondrial mRNAs by uridine addition and deletion generates conserved amino acid sequences and AUG initiation codons.

RNA editing is a novel type of mRNA processing in the kinetoplastid mitochondrion that involves the co- or posttranscriptional addition of uridine residues within transcripts. The result is an mRNA nucleotide sequence which differs from that of the corresponding gene. We have found that RNA editing may also occur through the deletion of genome-encoded uridines from the RNA sequence. Uridine additions and deletions in the 5' ends of the COIII, MURF2, and MURF3 transcripts create new N-terminal amino acid sequences that are conserved between species, and new AUG initiation codons in several cases. These results suggest that the creation of new amino acid sequences and methionine initiation codons may be important functions of RNA editing in the kinetoplastid mitochondrion.

Amino Acid Sequence↗

PubMed2005

Excitotoxicity and ALS: what is unique about the AMPA receptors expressed on spinal motor neurons?

It has been repeatedly reported that spinal motor neurons are selectively vulnerable to AMPA receptor-mediated excitotoxicity. Therefore, identifying the uniqueness of AMPA receptors that are expressed on motor neurons, especially in individuals affected with sporadic amyotrophic lateral sclerosis (ALS) is essential for elucidating the etiology of this disorder. The mechanism that initiates motor neuronal death appears to be an exaggerated influx of Ca(2+) through AMPA receptors. The determinants that affect this Ca(2+) influx are Ca(2+) permeability, which is regulated by the presence of the GluR2 subunit and by RNA editing at the Q/R site of GluR2; channel desensitization, which is regulated by alternative splicing at the flip/flop site and by RNA editing at the R/G site of GluR subunits; and receptor density on the cell surface, which is controlled by many factors including regulatory proteins, direct phosphorylation and RNA editing at the Q/R site. This review focuses on recent progress on the molecular dynamics of AMPA receptors and discusses the pathophysiology of selective motor neuron death mediated by AMPA receptors in individuals affected with sporadic ALS.

Amyotrophic Lateral Sclerosis↗

PubMed2002

Divergent intron conservation in the mitochondrial nad2 gene: signatures for the three bryophyte classes (mosses, liverworts, and hornworts) and the lycophytes.

The slow-evolving mitochondrial DNAs of plants have potentially conserved information on the phylogenetic branching of the earliest land plants. We present the nad2 gene structures in hornworts and liverworts and in the presumptive earliest-branching vascular land plant clade, the Lycopodiopsida. Taken together with the recently obtained nad2 data for mosses, each class of bryophytes presents another pattern of angiosperm-type introns conserved in nad2: intron nad2i1 in mosses; intron nad2i3 in liverworts; and both introns, nad2i3 and nad2i4, in hornworts. The lycopods Isoetes and Lycopodium show diverging intron conservation and feature a unique novel intron, termed nad2i3b. Hence, mitochondrial introns in general are positionally stable in the bryophytes and provide significant intraclade phylogenetic information, but the nad2 introns, in particular, cannot resolve the interclade relationships of the bryophyte classes and to the tracheophytes. The necessity for RNA editing to reconstitute conserved codon entities in nad2 is obvious for all clades except the marchantiid liverworts. Finally, we find that particularly small group II introns appear as a general feature of the Isoetes chondriome. Plant mitochondrial peculiarities such as RNA editing frequency, U-to-C type of RNA editing, and small group II introns appear to be genus-specific rather than gene-specific features.

Amino Acid Sequence↗

PubMed1997

Discrete determinants in transfer RNA for editing and aminoacylation.

During translation errors of aminoacylation are corrected in editing reactions which ensure that an amino acid is stably attached to its corresponding transfer RNA (tRNA). Previous studies have not shown whether the tRNA nucleotides needed for effecting translational editing are the same as or distinct from those required for aminoacylation, but several considerations have suggested that they are the same. Here, designed tRNAs that are highly active for aminoacylation but are not active in translational editing are presented. The editing reaction can be controlled by manipulation of nucleotides at the corner of the L-shaped tRNA. In contrast, these manipulations do not affect aminoacylation. These results demonstrate the segregation of nucleotide determinants for the editing and aminoacylation functions of tRNA.

Acetylation↗

PubMed1996

A ribosomal protein L2 gene is transcribed, spliced, and edited at one site in rice mitochondria.

The mitochondrial ribosomal protein L2 gene (rpl2) is coded by two exons of 840 and 669 bp separated by an intron sequence of 1481 bp in the rice mitochondrial genome. The rpl2 gene is located three nucleotides upstream of the ribosomal protein S19 gene (rps19) and both genes are co-transcribed. cDNA sequence analysis identified splicing of the intron sequence from the rpl2 mRNA as well as RNA editing events. The deduced secondary structure of the rpl2 intron sequence shows the characteristic features of a group-II intron. A single RNA editing site is identified in rpl2 and six editing sites in rps19 transcripts. In addition, one editing site is observed in the 3 nucleotide intergenic region. Analysis of individual cDNA clones showed a different extent of RNA editing. The rice rpl2 intron is located at a different site and shows no significant nucleotide sequence similarity with the rpl2 intron of liverwort. However, 60% nucleotide sequence identity is observed between the rice rpl2 intron and the Oenothera nad5 intron in a 234 nucleotide region. The mitochondrial rpl2 sequence is absent from the pea mitochondrial genome and we consequently propose that the mitochondrial RPL2 protein is encoded by a nuclear gene in pea.

Amino Acid Sequence↗