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RNA processing and the evolution of eukaryotes.

In eukaryotes, RNA processing events, including alternative splicing and RNA editing, can generate many different messages from a single gene. As a consequence, the RNA pool, which we refer to here as the 'ribotype', has a different information content from the genotype and can vary as circumstances change. The outcome of a single RNA processing event often regulates the outcome of another, giving rise to networks that affect the composition and expression of a particular ribotype. Successful ribotypes are determined by natural selection, and can be incorporated into the genome over time by reverse transcription. Eukaryotic evolution is therefore influenced by the alternate ways in which RNAs are processed and the continual interplay between RNA and DNA.

Animals↗

The guide RNA database (3.0).

The RNA editing process within the mitochondria of kinetoplastid organisms is controlled by small, trans -acting RNA molecules referred to as guide RNAs. The guide RNA database is a compilation of published guide RNA sequences, currently containing 254 entries from 11 different organisms. Additional information includes RNA secondary and tertiary structure models, information on the gene localisation, literature citations and other relevant facts. The database can be accessed through the World Wide Web (WWW) at http://www.biochem.mpg.de/ goeringe/

Animals↗

De novo protein synthesis is required for activation-induced cytidine deaminase-dependent DNA cleavage in immunoglobulin class switch recombination.

Activation-induced cytidine deaminase is required for the DNA cleavage step of Ig class switch recombination (CSR). However, its molecular mechanism is controversial. RNA-editing hypothesis postulates that activation-induced cytidine deaminase deaminates cytosine in an unknown mRNA to generate a new mRNA encoding an endonuclease for CSR and thus predicts that DNA cleavage depends on de novo protein synthesis. On the other hand, DNA deamination hypothesis proposes that DNA cleavage is initiated by cytosine deamination in DNA, followed by uracil removal by uracil DNA glycosylase. By using the chromatin immunoprecipitation assay to detect gamma-H2AX focus formation as a marker for DNA cleavage, we found that cycloheximide inhibited DNA cleavage in the Ig heavy-chain locus during CSR. Requirement of protein synthesis in the DNA cleavage step of CSR strengthens the RNA-editing hypothesis.

Animals↗

An ordered Arabidopsis thaliana mitochondrial cDNA library on high-density filters allows rapid systematic analysis of plant gene expression: a pilot study.

The availability of the complete sequence of a genome allows a systematic analysis of its expression. Gene-specific variations of transcription levels and phenomena such as transcript processing and RNA editing require large numbers of clones to be examined. For the completely sequenced mitochondrial genome of Arabidopsis thaliana we adapted robot technology to identify and characterize expressed genes. A cDNA library of about 50,000 clones was constructed, robot-ordered into 384-well microtitre plates and spotted onto high-density filter membranes. These filters permit the isolation of large numbers of specific cDNA clones in a single hybridization step. The cox1, cox2 and cox3 genes were used to evaluate the feasibility and efficiency of this approach. A cluster of RNA editing sites observed outside the cox3 coding region identifies a novel reading frame orf95 in higher plants with significant similarity to a subunit of respiratory chain complex II.

Arabidopsis↗

Recent advances in the study of AMPA receptors.

As glutamate is a dominant excitatory neurotransmitter in the central nervous system, glutamate receptors, and especially AMPA receptors, are located ubiquitously in all brain areas. In this paper, we reviewed recent advances of studies on AMPA receptor functions. AMPA receptors are cation-conducting complexes composed of various combinations of four subunits (GluR1 to GluR4). The glutamine residue located in the pore-forming segment of GluR2 subunit (Q/R site) is changed to arginine by RNA editing at the pre mRNA stage in normal adult mammalian animal. The edited GluR2 subunit is a major determination of Ca(2+) permeability of the AMPA receptor; only edited GluR2-lacking receptor shows high-Ca(2+) permeability. The assembly of glutamate AMPA receptor subunit is not completely according to the stochastic theory. The heteromeric subunits assembly is more rapid than the homomeric assembly is. The transfer of AMPA receptor subunit to the plasma membrane is conducted in multiple ways. Many molecules that interact with the intracellular domain of AMPA receptor subunits are reported as the modulators of AMPA receptor subunit transfer. In the motoneuron of sporadic amyotrophic lateral sclerosis (ALS) patients, the efficiency of RNA editing at the GluR2 Q/R site is significantly decreased. Relative low level of edited GluR2 subunit expression is likely responsible for motoneuronal death in ALS. Recently, AMPA receptors in glial cells have been studied. Bergmann glial cells in cerebellum express Ca(2+)-permeable AMPA receptors. Conversion of these AMPA receptors to Ca(2+)-impermeable type receptors induces morphological and functional changes. Glioblastoma cells also express Ca(2+)-permeable AMPA receptors, and their conversion to Ca(2+)-impermeable receptors inhibits cell locomotion and induces apoptosis.

Amyotrophic Lateral Sclerosis↗

Taking U out, with two nucleases?

BACKGROUND: REX1 and REX2 are protein components of the RNA editing complex (the editosome) and function as exouridylylases. The exact roles of REX1 and REX2 in the editosome are unclear and the consequences of the presence of two related proteins are not fully understood. Here, a variety of computational studies were performed to enhance understanding of the structure and function of REX proteins in Trypanosoma and Leishmania species. RESULTS: Sequence analysis and homology modeling of the Endonuclease/Exonuclease/Phosphatase (EEP) domain at the C-terminus of REX1 and REX2 highlights a common active site shared by all EEP domains. Phylogenetic analysis indicates that REX proteins contain a distinct subfamily of EEP domains. Inspection of three-dimensional models of the EEP domain in Trypanosoma brucei REX1 and REX2, and Leishmania major REX1 suggests variations of previously characterized key residues likely to be important in catalysis and determining substrate specificity. CONCLUSION: We have identified features of the REX EEP domain that distinguish it from other family members and hence subfamily specific determinants of catalysis and substrate binding. The results provide specific guidance for experimental investigations about the role(s) of REX proteins in RNA editing.

Binding Sites↗

Trypanosoma brucei minicircles encode multiple guide RNAs which can direct editing of extensively overlapping sequences.

Small guide RNAs (gRNAs) may direct RNA editing in kinetoplastid mitochondria. We have characterized multiple gRNA genes from Trypanosoma brucei (EATRO 164), that can specify up to 30% of the editing of the COIII, ND7, ND8, and A6 mRNAs and we have also found that the non-translated region of edited COIII mRNA of strain (EATRO 164) differs from that of another strain. Several of the gRNAs specify overlapping regions of the same mRNA often specifying sequence beyond that required for an anchor duplex with the next gRNA. Some gRNAs have different sequence but specify identical editing of the same region of mRNA. These data indicate a complex gRNA population and consequent complex pattern of editing in T. brucei.

Animals↗

Pervasive survival of expressed mitochondrial rps14 pseudogenes in grasses and their relatives for 80 million years following three functional transfers to the nucleus.

BACKGROUND: Many mitochondrial genes, especially ribosomal protein genes, have been frequently transferred as functional entities to the nucleus during plant evolution, often by an RNA-mediated process. A notable case of transfer involves the rps14 gene of three grasses (rice, maize, and wheat), which has been relocated to the intron of the nuclear sdh2 gene and which is expressed and targeted to the mitochondrion via alternative splicing and usage of the sdh2 targeting peptide. Although this transfer occurred at least 50 million years ago, i.e., in a common ancestor of these three grasses, it is striking that expressed, nearly intact pseudogenes of rps14 are retained in the mitochondrial genomes of both rice and wheat. To determine how ancient this transfer is, the extent to which mitochondrial rps14 has been retained and is expressed in grasses, and whether other transfers of rps14 have occurred in grasses and their relatives, we investigated the structure, expression, and phylogeny of mitochondrial and nuclear rps14 genes from 32 additional genera of grasses and from 9 other members of the Poales. RESULTS: Filter hybridization experiments showed that rps14 sequences are present in the mitochondrial genomes of all examined Poales except for members of the grass subfamily Panicoideae (to which maize belongs). However, PCR amplification and sequencing revealed that the mitochondrial rps14 genes of all examined grasses (Poaceae), Cyperaceae, and Joinvilleaceae are pseudogenes, with all those from the Poaceae sharing two 4-NT frameshift deletions and all those from the Cyperaceae sharing a 5-NT insertion (only one member of the Joinvilleaceae was examined). cDNA analysis showed that all mitochondrial pseudogenes examined (from all three families) are transcribed, that most are RNA edited, and that surprisingly many of the edits are reverse (U-->C) edits. Putatively nuclear copies of rps14 were isolated from one to several members of each of these three Poales families. Multiple lines of evidence indicate that the nuclear genes are probably the products of three independent transfers. CONCLUSION: The rps14 gene has, most likely, been functionally transferred from the mitochondrion to the nucleus at least three times during the evolution of the Poales. The transfers in Cyperaceae and Poaceae are relatively ancient, occurring in the common ancestor of each family, roughly 80 million years ago, whereas the putative Joinvilleaceae transfer may be the most recent case of functional organelle-to-nucleus transfer yet described in any organism. Remarkably, nearly intact and expressed pseudogenes of rps14 have persisted in the mitochondrial genomes of most lineages of Poaceae and Cyperaceae despite the antiquity of the transfers and of the frameshift and RNA editing mutations that mark the mitochondrial genes as pseudogenes. Such long-term, nearly pervasive survival of expressed, apparent pseudogenes is to our knowledge unparalleled in any genome. Such survival probably reflects a combination of factors, including the short length of rps14, its location immediately downstream of rpl5 in most plants, and low rates of nucleotide substitutions and indels in plant mitochondrial DNAs. Their survival also raises the possibility that these rps14 sequences may not actually be pseudogenes despite their appearance as such. Overall, these findings indicate that intracellular gene transfer may occur even more frequently in angiosperms than already recognized and that pseudogenes in plant mitochondrial genomes can be surprisingly resistant to forces that lead to gene loss and inactivation.

Cell Nucleus↗

Is there any sense in antisense editing?

Several recent studies have hypothesized that sense-antisense RNA-transcript pairs create dsRNA duplexes that undergo extensive A-to-I RNA editing. We studied human and mouse genomic antisense regions and found that the editing level in these areas is negligible. This observation questions the scope of sense-antisense duplexes formation in-vivo, which is the basis for several proposed regulatory mechanisms.

Alu Elements↗

Biochemical analysis and scanning force microscopy reveal productive and nonproductive ADAR2 binding to RNA substrates.

Scanning force microscopy (SFM) can be used to image biomolecules at high resolution. Here we demonstrate that single-molecule analysis by SFM complements biochemical data on RNA protein binding and can provide information that cannot be obtained by the usual biochemical methods. We have used this method to study the interaction between the RNA editing enzyme ADAR2 and RNA transcripts containing selective and nonselective editing sites. The natural selectively edited R/G site from glutamate receptor subunit B (GluR-B) was inserted into an RNA backbone molecule consisting of a completely double-stranded (ds) central part and incompletely paired ends derived from potato spindle tuber viroid (PSTVd). This molecule was efficiently edited at the R/G site, but promiscuous editing occurred at nonselective sites in the completely double-stranded region. The construct was also used to analyze binding of ADAR2 to wild-type and modified R/G editing sites in relation to binding at other nonselectively edited sites. Editing analysis together with SFM allow us to differentiate between binding and enzymatic activity. ADAR2 has been reported to have a general affinity to dsRNA. However, we show that there is a prominent bias for stable binding at sites selectively edited over other edited sites. On the other hand, promiscuous editing at nonselective sites apparently results from transient binding of the enzyme to the substrate. Furthermore, we find distinct sites with nonproductive binding of the enzyme.

Adenosine Deaminase↗

The molecular biology of hepatitis delta virus.

Hepatitis delta virus (HDV) contains a circular, viroid-like RNA genome, the only animal viral RNA of its kind. It possesses a ribozyme activity, which can autocatalytically cleave and ligate itself. The ribozyme has a unique structural requirement different from other known ribozymes. HDV RNA undergoes RNA-dependent RNA replication via a double rolling circle mechanism, which is probably mediated by cellular RNA polymerase II, utilizing modified cellular transcription machineries. HDV RNA encodes a single protein, hepatitis delta antigen, which is a nuclear, RNA-binding phosphoprotein and required for viral RNA replication. During replication, HDV RNA undergoes a specific RNA editing event to extend its open reading frame and produce a longer, isoprenylated delta antigen, which suppresses RNA replication and initiates viral particle assembly. Ribozyme, cell-mediated RNA-dependent RNA replication, and RNA editing are some of the unique properties and unresolved issues of the molecular biology of HDV.

Animals↗

Translation of the edited mRNA for cytochrome b in trypanosome mitochondria.

The type of RNA editing found in the kinetoplast-mitochondria of trypanosomes and related protozoa, involving uridylate insertions and deletions, creates translatable messenger RNAs (mRNAs) out of nonsense pre-edited RNAs by correcting encoded defects that vary from simple frameshifts to large "cryptic" regions. However, any evidence for translation of these mRNAs in the kinetoplast has been missing for decades. We identified a kinetoplast-encoded protein, apocytochrome b, whose mRNA is edited in the 5' region. The determined amino-terminal sequence of the protein coincides with the predicted sequence derived from the edited region, demonstrating that the cognate apocytochrome b mRNA is translated into a functional protein. This finding represents the first direct evidence for a functional translation system in the kinetoplasts.

Amino Acid Sequence↗

Differences in editing at homologous sites in messenger RNAs from angiosperm mitochondria.

Recent work has shown that amino acid sequence comparisons can be used to infer sites of C-to-U RNA editing in plant mitochondrial mRNAs (1). In order to test such predictions further and to search for conserved mRNA structural motifs that might provide insight into the mechanism of recognition of editing sites, the complete sequences of the cytochrome c oxidase subunit II (COXII) mRNAs of wheat, maize and pea were determined by reverse transcriptase sequencing. The results affirm the high reliability of editing predictions based on amino acid sequence alignments, and prompt us to make the further inference that COXI (cytochrome oxidase subunit I) mRNA is extensively edited in dicotyledonous plants but not in monocotyledons. In plant COXII mRNAs, additional non-predicted editing occurs such that the resulting derived amino acid sequences are more similar to those of non-plants than is indicated by the respective plant COXII DNA sequences. A number of homologous sites show differences in editing among species, and certain positions show partial editing within a species. Despite some deviation from expected nucleotide frequencies in the vicinity of editing sites, no extensive conserved primary or secondary structural motifs are apparent. The relevance of these data to the mechanism of RNA editing in plant mitochondria is discussed.

Amino Acid Sequence↗

A cytidine deaminase expressed in the post-infective L3 stage of the filarial nematode, Brugia pahangi, has a novel RNA-binding activity.

A number of genes have been identified that are highly expressed in the post-infective L3 stage of the filarial parasite, Brugia pahangi. Amongst these was a cDNA with homology to the cytidine deaminase (CDD) gene family. Phylogenetic analysis of the various cytosine nucleoside deaminases suggest that Brugia pahangi CDD evolved with significant divergence from the RNA editing family. In order to characterize its function, we have expressed Brugia pahangi CDD in bacteria as a chimera with maltose-binding protein (MBP). Biochemical analysis demonstrates the MBP-CDD fusion protein functions as an authentic cytidine deaminase with an obligate requirement for zinc. In addition to cytidine deaminase activity, however, the fusion protein demonstrates RNA binding activity with specificity for AU-rich sequences and was found to bind an RNA template spanning the edited site of mammalian apolipoprotein B (apoB) mRNA. This RNA binding activity was not found in two different recombinant bacterial CDD proteins. In vitro RNA editing assays revealed that MBP-CDD failed to mediate cytidine deamination of a mammalian apoB RNA template. Furthermore, binding of MBP-CDD to the apoB RNA did not inhibit in vitro editing of this template by apobec-1. The data suggest that the cytosine nucleoside deaminases and RNA editing deaminases have acquired different mechanisms of binding to an AU-rich RNA template, presumably with different functional implications.

Amino Acid Sequence↗

Characterization and comparative analysis of the complete mitochondrial genome sequence of Aucklandia lappa Decne.

BACKGROUND: Aucklandia lappa Decne, a precious medicinal herb in China, utilises the dried rhizome as its medicinal part, which riches in volatile oils, sesquiterpene compounds and other active constituents. Although the mitogenome of A. lappa has been assembled, related research remains in its preliminary stages, far from achieving comprehensive and in-depth understanding. RESULTS: In this paper, the complete mitogenome of A. lappa was assembled by employing a hybrid strategy that combined Illumina short-read and Nanopore long-read sequencing. The assembled mitogenome is 436,648 bp in size with a GC content of 45.06%. The mitogenome has only one chromosomal structure, It contains 54 genes, including 31 protein-coding genes(PCG), 19 tRNA genes, and 4 rRNA genes. A total of 32 high-frequency codons exhibiting significant AT-bias, 431 RNA editing sites, and 26 homologous fragments were transferred from the chloroplast to mitochondria genes (7,337 bp, 1.68%). Furthermore, we conducted a phylogenetic analysis involving in A. lappa and 27 other taxa to clarify its evolutionary and taxonomic status. These findings provide a foundation for further understanding the evolutionary relationships within Asteraceae plant. CONCLUSION: Through the assembly and comprehensive analysis of A. lappa mitogenome, This study has for the first time fully elucidated its mitogenomic structural characteristics.These results not only provide high-quality genetic resources for research on the Asteraceae mitogenome but also lay a solid foundation for in-depth exploration of the evolution and functional genomics of medicinal plants in the Asteraceae family.

Genome, Mitochondrial↗

Editing site recognition and nucleotide insertion are separable processes in Physarum mitochondria.

Insertional RNA editing in Physarum polycephalum is a complex process involving the specific addition of non-templated nucleotides to nascent mitochondrial transcripts. Since all four ribonucleotides are substrates for the editing activity(s), both the site of insertion and the identity of the nucleotide to be added at a particular position must be specified, but the signals for these events have yet to be elucidated. Here we report the occurrence of sporadic errors in RNAs synthesized in vitro. These mistakes, which include omission of encoded nucleotides as well as misinsertions, occur only on templates that support editing. The pattern of these misediting events indicates that editing site recognition and nucleotide addition are separable events, and that the recognition step involves features of the mitochondrial template that are required for editing. The larger deletions lack all templated nucleotides between editing sites, suggesting that the transcription/editing apparatus can "jump" from one insertion site to another, perhaps mediated by interactions with editing determinants, while smaller omissions most likely reflect misalignment of the transcript upon resumption of templated RNA synthesis.

Animals↗

DNA sequence analysis of the complete mitochondrial genome of the green alga Scenedesmus obliquus: evidence for UAG being a leucine and UCA being a non-sense codon.

The complete DNA sequence of the mitochondrial genome of the chlorophyceen alga Scenedesmus obliquus was determined. The circular genome of 42781bp contains a basic set of 13 mitochondrial genes, which are conserved among plant or algal chondriomes. In addition, two scrambled rRNA and 27 tRNA genes are present, together with four intronic sequences (group I and II) and five open reading frames (ORFs), which show no significant homology to other ORFs from organellar genomes. The comparison with deduced amino acid sequences from 13 conserved mitochondrial genes gives rise to the conclusion that two deviations from the standard genetic code must be present in S. obliquus mitochondria: (i) UAG codes for leucine as was already found in some other algal mitochondria; (ii) UCA is a stop codon, which seems unique for mitochondrial genomes. This was supported by our finding that a tRNA-Leu gene possesses a UCA anticodon and by a missing tRNA-serine, able to decode the UCA codon. Consistent with these data is the absence of any UCA codon from conserved mitochondrial ORFs. This codon occurs only close to the end of all ORFs, while UAA or UGA codons are found at some distance from any conserved ORF. Codon changes by RNA editing can be excluded, since RT-PCR analysis does not reveal any evidence for post-transcriptional RNA modifications of the primary transcript.

Algal Proteins↗

From gene to protein in higher plant mitochondria.

Higher plant mitochondria contain a genetic system with a genome, transcription and translation processes, which have to be logistically integrated with the two other genomes in the nucleus and the plastid. In plant mitochondria, after transcripts have been synthesised, at least in some cases by a phage-type RNA polymerase, they have to go through a complex processing apparatus, which depends on protein factors imported from the cytosol. Processing involves cis- and trans-splicing, internal RNA editing and maturation at the transcript termini, these steps often occurring in parallel. Transcript life is terminated by RNA degradation mechanisms, one of which involves polyadenylation. RNA metabolism seems to be a key element of the regulation of gene expression in higher plant mitochondria.

Genome, Plant↗