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PubMed2002

A hammerhead ribozyme substrate and reporter for in vitro kinetoplastid RNA editing.

Current in vitro assays for RNA editing in kinetoplastids directly examine the products generated by incubation of pre-mRNA substrate with guide RNA (gRNA) and mitochondrial (mt) extract. RNA editing substrates that are modeled on hammerhead ribozymes were designed with catalytic cores that contained or lacked additional uridylates (Us). They proved to be sensitive reporters of editing activity when used for in vitro assays. A deletion editing substrate that is based on A6 pre-mRNA had no ribozyme activity, but its incubation with gRNA and mt extract resulted in its deletion editing and production of a catalytically active ribozyme. Hammerhead ribozymes are thus sensitive tools to assay in vitro RNA editing.

Animals↗

PubMed1993

RNA editing: exploring one mode with apolipoprotein B mRNA.

RNA editing is a newly described genetic phenomenon. It encompasses widely different molecular mechanisms and events. According to the specific RNA modification, RNA editing can be broadly classified into six major types. Type II RNA editing occurs in plants and mammals; it consists predominantly in cytidine to uridine conversions resulting from deamination/transamination or transglycosylation, although in plants other mechanisms have not been excluded. Apolipoprotein B mRNA editing is the only well-documented editing phenomenon in mammals. It is an intranuclear event that occurs posttranscriptionally, coincident with splicing and polyadenylation. Recent observations indicate that the tissue- and sequence-specific process is mediated by an enzyme that has separate domains for editing and sequence recognition. The presence of apolipoprotein B mRNA editing activity in tissues that do not produce the protein suggests that other RNAs may be edited and RNA editing may be a genetic phenomenon of general biological importance to the cell.

APOBEC-1 Deaminase↗

PubMed1997

Kinetoplastid RNA editing: complexes and catalysts.

RNA editing in kinetoplastids involves post-transcriptional insertion and deletion of uridylates (Us) to produce mature mitochondrial mRNAs with sequences specified by trans acting small guide RNAs. In vitro studies indicate the reaction pathway involves endonucleolytic cleavage of the precursor mRNA at the editing site, uridylate addition or removal at the 3' end of the 5' cleavage product, followed by ligation to the 3' cleavage product. This editing is catalyzed by a macromolecular complex that is in the early stages of characterization. Recent studies have resolved the general mechanism of editing, and show that editing occurs in association with a macromolecular complex.

Animals↗

PubMed1998

RNA editing in the free-living bodonid Bodo saltans.

In parasitic kinetoplastid protozoa, mitochondrial (mt) mRNAs are post-transcriptionally edited by insertion and deletion of uridylate residues, the information being provided by guide (g) RNAs. In order to further explore the role and evolutionary history of this process, we searched for editing in mt RNAs of the free-living bodonid Bodo saltans. We found extensive editing in the transcript for NADH dehydrogenase (ND) subunit 5, which is unedited in trypanosomatids. In contrast, B.saltans cytochrome c oxidase (cox) subunit 2 and maxicircle unidentified reading frame (MURF) 2 RNAs display limited editing in the same regions as their trypanosomatid counterparts. A putative intramolecular cox2 gRNA and the gene for gMURF2-I directing the insertion of only one U in the 5' editing domain of MURF2 RNA, are conserved in B.saltans. This lends (further) evolutionary support to the proposed role of these sequences as gRNAs. Phylogenetic analysis showed that B.saltans is more closely related to trypanosomatids than the cryptobiids Trypanoplasma borreli and Cryptobia helicis, in line with the trypanosomatid-like cox2 and MURF2 RNA editing patterns. Nevertheless, other features like the apparent absence of a catenated mtDNA network, are shared with bodonid and cryptobiid species. ND5 RNA editing may represent yet another example of editing 'on the way out' during kinetoplastid evolution, but in view of the fact that cox2 RNA is unedited in T. borreli and C.helicis, we infer that the editing of this RNA may have arisen relatively recently. Our results provide the first examples of RNA editing in a free-living kinetoplastid, indicating that there is no direct link between U-insertion/deletion editing and a parasitic lifestyle.

Amino Acid Sequence↗

PubMed2002

Trypanosome mitochondrial 3' terminal uridylyl transferase (TUTase): the key enzyme in U-insertion/deletion RNA editing.

A 3' terminal RNA uridylyltransferase was purified from mitochondria of Leishmania tarentolae and the gene cloned and expressed from this species and from Trypanosoma brucei. The enzyme is specific for 3' U-addition in the presence of Mg(2+). TUTase is present in vivo in at least two stable configurations: one contains a approximately 500 kDa TUTase oligomer and the other a approximately 700 kDa TUTase complex. Anti-TUTase antiserum specifically coprecipitates a small portion of the p45 and p50 RNA ligases and approximately 40% of the guide RNAs. Inhibition of TUTase expression in procyclic T. brucei by RNAi downregulates RNA editing and appears to affect parasite viability.

Animals↗

PubMed2003

A site-specific factor interacts directly with its cognate RNA editing site in chloroplast transcripts.

RNA editing involves a variety of genetic systems and occurs by different mechanisms. In higher plant chloroplasts, specific sites of some transcripts are subject to C-to-U conversion. We have previously shown that site-specific trans-acting factors for psbE and petB mRNA editing bind corresponding cis-elements, which are located 5 nucleotides upstream from the editing site. Here we report that, by using mRNAs labeled either at the center of the upstream cis-element or at the editing site, the site-specific factors can be cross-linked with nucleotides at both positions. Mutations of nucleotides in the proximal region of the editing site revealed a correlation between editing activity and cross-linking efficiency of factors with the editing site, even though cross-linking with the upstream cis-element was unaffected. These observations suggest that the site-specific factor binds stably to the upstream ciselement, whereas it interacts weakly with the editing site. This finding raises the intriguing possibility that the site-specific factor is involved in both site-determination and C-to-U conversion in chloroplast RNA editing.

Base Sequence↗

PubMed2005

Altered RNA editing of serotonin 2C receptor in a rat model of depression.

Altered RNA editing of serotonin 2C receptor (HTR2C) has been suggested to be involved in the pathophysiology of major depression. Here we examined RNA editing status of HTR2C in the learned helplessness (LH) rats, one of well-established animal models of depression. LH rats showed the significantly increased RNA editing of site E, and tendency for increased RNA editing of other editing sites. Treatment with fluoxetine, a selective serotonin reuptake inhibitor, or imipramine, a tricyclic antidepressant, affected the RNA editing status of the LH rats. Although, these antidepressants differentially altered RNA editing status, they commonly reduced RNA editing efficiency of site E. We further revealed that altered RNA editing in the LH rats and by antidepressants was not explained by altered expression of RNA editing enzymes or their substrates (adenosine deaminases that act on RNA, HTR2C, and spliced form of HTR2C). These results suggest that alteration of RNA editing of HTR2C may play a role in the pathophysiology of depression and action of antidepressants.

Adenosine Deaminase↗

PubMed1992

RNA editing in trypanosomes. The us(e) of guide RNAs.

Guide RNAs are encoded in maxicircle and minicircle DNA of trypanosome mitochondria. They play a pivotal role in RNA editing, a process during which the nucleotide sequence of mitochondrial RNAs is altered by U-insertion and deletion. Guide RNAs vary in length from 35 to 78 nucleotides, which correlates with the variation in length of the three functionally important regions of which they are composed: (i) a 4-14 nucleotide 'anchor' sequence embedded in the 5' region, which is complementary to a target sequence on the pre-edited RNA downstream of an editing domain, (ii) a middle part containing the editing information, which ranges from guiding the insertion of just one U into one site to that of the insertion of 32 Us into 10 sites, and (iii) a 5-24 nucleotide 3' terminal oligo [U] extension. Moreover, a variable uridylation site creates gRNAs containing a varying segment of editing information for the same domain. Comparison of different guide RNAs demonstrates that, besides the U-tail, they have no obvious common primary and secondary sequence motifs, each particular sequence being unique. The occurrence in vivo and the synthesis in vitro of chimeric molecules, in which a guide RNA is covalently linked through its 3' U-tail to an editing site of a pre-edited RNA, suggests that RNA editing occurs by consecutive transesterification reactions and is evidence that the guide RNAs not only provide the genetic information, but also the Us themselves.

Animals↗

PubMed2006

RNA editing has been lost in the mitochondrial cox3 and rps13 mRNAs in Asparagales.

RNA editing in plant mitochondria alters the RNA sequence by converting C-to-U or U-to-C at a specific site. We investigated the requirement for RNA editing in the complete genomic sequences of the gene encoding the cytochrome oxidase subunit III (cox3) and the ribosomal protein S13 (rps13) in 59 closely related species within the Asparagales and Liliales (monocots). To obtain a comprehensive picture of the degree of variation in editing we explored the non-synonymous RNA editing sites within the newly sequenced cox3 and rps13 genes by a comparative phylogenetic approach. RNA editing is predicted to occur in all the surveyed species, but to different extents. Zero to one non-synonymous editing site is inferred in the cox3 mRNA in species from Amaryllidaceae and Iridaceae. No RNA editing of rps13 mRNAs is required in Amaryllidaceae, because all respective genomic sequences resemble the edited version of the mRNAs of other analysed land plants. The observed absence of cox3 and rps13 RNA editing in Iridaceae and Amaryllidaceae and the striking RNA editing reduction of ccb2 in the latter family is likely generated by recombination and reverse transcription mediated events involving edited mitochondrial transcripts.

Amino Acid Sequence↗

PubMed2000

Conservation of RNA editing between rice and maize plastids: are most editing events dispensable?

The extent of conservation of RNA editing sites in the plastid genome of rice was determined by comparing the genomic sequence with that of the cDNA. The presence of a T in the cDNA predicted to be a C by the DNA sequence of the plastid genome, indicated C to U editing. In the 11 plastid transcripts of rice a total of 21 editing sites were found. In maize, a closely related grass species, 26 editing sites have been reported in 13 plastid transcripts. Most editing sites are conserved between the two species, although differences in RNA editing were found at eight sites. In seven cases the T was already encoded at the DNA level, eliminating the requirement for RNA editing. In one case (rpoB, codon 206) the RNA sequence was conserved between the two species, but the mRNA is still not edited in rice. It appears that, although evolutionarily conserved, RNA editing is essential only for a few plastid editing sites. Information about RNA editing in rice plastids will facilitate the design of plastid vectors with broad applicability in grass species.

DNA-Directed RNA Polymerases↗

PubMed2005

Reconstitution of uridine-deletion precleaved RNA editing with two recombinant enzymes.

Uridine insertion/deletion RNA editing in trypanosomatid mitochondria is a posttranscriptional RNA modification phenomenon required for translation of mitochondrial mRNAs. This process involves guide RNA-mediated cleavage at a specific site, insertion or deletion of Us from the 3' end of the 5' mRNA fragment, and ligation of the two mRNA fragments. The Leishmania major RNA ligase-containing complex protein 2 expressed in insect cells has a 3'-5' exoribonuclease activity and was therefore renamed RNA editing exonuclease 1 (REX1). Recombinant REX1 specifically trims 3' overhanging Us and stops at a duplex region. Evidence is presented that REX1 is responsible for deletion of the 3' overhanging Us from the bridged mRNA 5' cleavage fragment and that RNA editing ligase 1 is responsible for the ligation of the two mRNA cleavage fragments in U-deletion editing. The evidence involves both in vivo down-regulation of REX1 expression in Trypanosoma brucei by RNA interference and the reconstitution of precleaved U-deletion in vitro editing with only two recombinant enzymes: recombinant REX1 and recombinant RNA editing ligase 1.

Animals↗

PubMed2002

RNA editing: complexity and complications.

RNA editing in Trypanosomatids creates functional mitochondrial mRNAs by extensive uridylate (U) insertion and deletion as specified by small guide RNAs (gRNAs). Editing is catalysed by the multiprotein editosome. Over 20 of its protein components have been identified and additional proteins are likely to function in editing and its regulation. The functions of only a few editosome proteins have been determined. Surprisingly, there are related pairs or sets of editosome proteins, and insertion and deletion editing appear to be functionally and perhaps spatially separate. A model for the editosome is proposed, which has a catalysis domain with separate sectors for insertion and deletion editing. It also contains domains for anchor duplex and upstream RNA binding, which position the sequence to be edited in the catalysis domain.

Animals↗

PubMedDate not supplied

Sense from nonsense: how the genetic information of chloroplasts is altered by RNA editing.

Plastid transcripts can be subject to an RNA processing mechanism changing the identity of individual nucleotides and thus altering the information content of the mRNA. This processing step was termed RNA editing and adds a novel mechanism to the multitude of RNA maturation events required before mRNAs can serve as faithful templates in plastid protein biosynthesis. RNA editing in chloroplasts proceeds by the conversion of individual cytidine residues to uridine and, in some bryophytes, also by the reverse event, uridine-to-cytidine transitions. The discovery of RNA editing in chloroplasts has provided researchers with a wealth of molecular and evolutionary puzzles, many of which are not yet solved. However, recent work employing chloroplast transformation technologies has shed some light on the molecular mechanisms by which RNA editing sites are recognized with extraordinarily high precision. Also, extensive phylogenetic studies have provided intriguing insights in the evolutionary dynamics with which editing sites may come and go. This review summarizes the state-of-the-art in the field of chloroplast RNA editing, discusses mechanistic and evolutionary aspects of editing and points out some of the important open questions surrounding this enigmatic RNA processing step.

Base Sequence↗

PubMed1994

Evolution of RNA editing in kinetoplastid protozoa.

The editing of RNA in trypanosomatid mitochondria involves the insertion and occasional deletion of uridine residues within coding regions of maxicircle messenger RNA transcripts. The extent to which the transcripts of homologous genes undergo editing differs in different species. In some, entire genes are edited (pan-editing), whereas in others, editing is limited to the 5' termini of editing domains (5' editing). Here we investigate which type of editing is ancestral and which is derived, by analysing RNA editing in the different lineages, using a kinetoplastid phylogeny reconstructed from nuclear small subunit ribosomal RNA sequences. We conclude that the ancestral cryptogenes were pan-edited, and we hypothesize that the 5'-edited homologues were generated by several independent events from partially edited RNAs, in which case editing may be a more primitive mechanism than previously thought.

Adenosine Triphosphatases↗

PubMed2001

ARCD-1, an apobec-1-related cytidine deaminase, exerts a dominant negative effect on C to U RNA editing.

Mammalian apolipoprotein B (apoB) C to U RNA editing is catalyzed by a multicomponent holoenzyme containing a single catalytic subunit, apobec-1. We have characterized an apobec-1 homologue, ARCD-1, located on chromosome 6p21.1, and determined its role in apoB mRNA editing. ARCD-1 mRNA is ubiquitously expressed; phylogenetic analysis reveals it to be a distant member of the RNA editing family. Recombinant ARCD-1 demonstrates cytidine deaminase and apoB RNA binding activity but does not catalyze C to U RNA editing, either in vitro or in vivo. Although not competent itself to mediate deamination of apoB mRNA, ARCD-1 inhibits apobec-1-mediated C to U RNA editing. ARCD-1 interacts and heterodimerizes with both apobec-1 and apobec-1 complementation factor (ACF) and localizes to both the nucleus and cytoplasm of transfected cells. Together, the data suggest that ARCD-1 is a novel cytidine deaminase that interacts with apobec-1 and ACF to inhibit apoB mRNA editing, possibly through interaction with other protein components of the apoB RNA editing holoenzyme.

APOBEC-1 Deaminase↗

PubMed1994

Phylogenetic analysis of RNA editing: a primitive genetic phenomenon.

RNA editing by extensive uridine addition and deletion creates over 90% of the amino acid codons in the cytochrome-c oxidase subunit III (COIII) transcript in Trypanosoma brucei and Herpetomonas, whereas editing of the COIII transcripts in Leishmania tarentolae and Crithidia fasciculata generates only 6% of the amino acid codons and is limited to the 5' ends. Is extensive RNA editing a primitive or derived character? We constructed a phylogenetic tree based on nuclear small-subunit and mitochondrial large- and small-subunit ribosomal RNA sequences for nine species of kinetoplastid protozoa. Our results suggest that extensive editing is a primitive genetic phenomenon that has disappeared in recent evolutionary time and also that there have been multiple losses of the digenetic lifestyle by loss of the vertebrate host in parasite evolution.

Animals↗

PubMed2004

Interferon-alpha stimulation of liver cells enhances hepatitis delta virus RNA editing in early infection.

BACKGROUND/AIMS: RNA editing controls the formation of hepatitis-delta-antigen-S and -L and therefore plays a central role in the hepatitis-delta-virus (HDV) life-cycle. Editing is catalyzed by the enzyme Adenosine-deaminase-acting-on-RNA1 (ADAR1) of which two different forms, ADAR1-L and ADAR1-S, exist. As ADAR1-L is induced by interferon (IFN)-alpha, we examined the influence of IFN-alpha-stimulation of host cells on HDV-RNA editing. METHODS: Editing was studied in Huh-7-cells transfected with HDV-RNA on days 7, 14, 21 and 28 after transfection. ADAR1-L mRNA was measured by RT-PCR. RESULTS: IFN-alpha-treatment led to a 5-fold higher expression of ADAR1-L and to an increase in editing from 14+/-2% (SD) in unstimulated controls to 27+/-4% (SD) on day 7 after transfection. Editing further increases over time to the same maximum level of 35% in IFN-alpha-treated as well as untreated cells. CONCLUSIONS: By IFN-alpha-stimulation both ADAR1-L expression and editing are increased in Huh-7-cells at day 7, and the maximum level of edited antigenomes is reached earlier with IFN-alpha-treatment as compared to untreated cells. Thus, ADAR1-L appears to be able to increase editing, but the HDV genome apparently has an intrinsic negative feed-back regulation mechanism that limits editing to roughly a third of the genomes.

Adenosine Deaminase↗

PubMed1999

Nuclear genes from Tx CMS maintainer lines are unable to maintain atp6 RNA editing in any anther cell-type in the sorghum bicolor A3 cytoplasm.

RNA editing and cytoplasmic male sterility are two important phenomena associated with higher plant mitochondria. We recently have shown a potential function of RNA editing in CMS development. The frequency of atp6 RNA editing was specifically reduced in anthers of male-sterile Sorghum bicolor, which increased in frequency in partially restored progeny. Here we present data that show that the loss of RNA editing capability also occurs in a second nuclear background that allows the expression of male sterility. Loss of RNA editing thus appears to be associated with unique combinations of male-sterile cytoplasm and non-restoring nuclear backgrounds. In addition, the reduction of RNA editing affects both gametophytic and sporophytic anther cell-types but not other floral tissues. An analysis of F(2) plants exhibiting different levels of fertility indicates a co-segregation of fertility restoration and atp6 RNA editing. The atp6 transcript abundance is similar in seedlings and anthers of male-sterile, partially restored, and male-fertile lines and thus is not associated with loss of atp6 RNA editing in anthers. A model for RNA editing and male sterility based on the data available is presented. Functional correlations with other CMS systems are also discussed.

Cell Nucleus↗