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Synthetic substrate analogs for the RNA-editing adenosine deaminase ADAR-2.

Yi-Brunozzi, H Y; Easterwood, L M; Kamilar, G M; Beal, P A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/07/1999 EN
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We have synthesized structural analogs of a natural RNA editing substrate and compared editing reactions of these substrates by recombinant ADAR-2, an RNA-editing adenosine deaminase. Deamination rates were shown to be sensitive to structural changes at the 2[prime]-carbon of the edited adenosine. Methylation of the 2[prime]-OH caused a large decrease in deamination rate, whereas 2[prime]-deoxyadenosine and 2[prime]-deoxy-2[prime]-fluoroadenosine were deaminated at a rate similar to adenosine. In addition, a duplex containing as few as 19 bp of the stem structure adjacent to the R/G editing site of the GluR-B pre-mRNA supports deamination of the R/G adenosine by ADAR-2. This identification and initial characterization of synthetic RNA editing substrate analogs further defines structural elements in the RNA that are important for the deamination reaction and sets the stage for additional detailed structural, thermodynamic and kinetic studies of the ADAR-2 reaction.

An ADAR that edits transcripts encoding ion channel subunits functions as a dimer

Gallo, Angela; Keegan, Liam P.; Ring, Gillian M.; O’Connell, Mary A.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Publicado em 01/07/2003 EN
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In this report, we establish that Drosophila ADAR (adenosine deaminase acting on RNA) forms a dimer on double-stranded (ds) RNA, a process essential for editing activity. The minimum region required for dimerization is the N-terminus and dsRNA-binding domain 1 (dsRBD1). Single point mutations within dsRBD1 abolish RNA-binding activity and dimer formation. These mutations and glycerol gradient analysis indicate that binding to dsRNA is important for dimerization. However, dimerization can be uncoupled from dsRNA-binding activity, as a deletion of the N-terminus (amino acids 1–46) yields a monomeric ADAR that retains the ability to bind dsRNA but is inactive in an editing assay, demonstrating that ADAR is only active as a dimer. Different isoforms of ADAR with different editing activities can form heterodimers and this can have a significant effect on editing in vitro as well as in vivo. We propose a model for ADAR dimerization whereby ADAR monomers first contact dsRNA; however, it is only when the second monomer binds and a dimer is formed that deamination occurs.

Specificity of ADAR-mediated RNA editing in newly identified targets

Riedmann, Eva M.; Schopoff, Sandy; Hartner, Jochen C.; Jantsch, Michael F.
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /06/2008 EN
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Adenosine deaminases that act on RNA (ADARs) convert adenosines to inosine in both coding and noncoding double-stranded RNA. Deficiency in either ADAR1 or ADAR2 in mice is incompatible with normal life and development. While the ADAR2 knockout phenotype can be attributed to the lack of editing of the GluR-B receptor, the embryonic lethal phenotype caused by ADAR1 deficiency still awaits clarification. Recently, massive editing was observed in noncoding regions of mRNAs in mice and humans. Moreover, editing was observed in protein-coding regions of four mRNAs encoding FlnA, CyFip2, Blcap, and IGFBP7. Here, we investigate which of the two active mammalian ADAR enzymes is responsible for editing of these RNAs and whether any of them could possibly contribute to the phenotype observed in ADAR knockout mice. Editing of Blcap, FlnA, and some sites within B1 and B2 SINEs clearly depends on ADAR1, while other sites depend on ADAR2. Based on our data, substrate specificities can be further defined for ADAR1 and ADAR2. Future studies on the biological implications associated with a changed editing status of the studied ADAR targets will tell whether one of them turns out to be directly or indirectly responsible for the severe phenotype caused by ADAR1 deficiency.

Engineered Alterations in RNA Editing Modulate Complex Behavior in Drosophila: REGULATORY DIVERSITY OF ADENOSINE DEAMINASE ACTING ON RNA (ADAR) TARGETS*

Jepson, James E. C.; Savva, Yiannis A.; Yokose, Chio; Sugden, Arthur U.; Sahin, Asli; Reenan, Robert A.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Select proteins involved in electrical and chemical neurotransmission are re-coded at the RNA level via the deamination of particular adenosines to inosine by adenosine deaminases acting on RNA (ADARs). It has been hypothesized that this process, termed RNA editing, acts to “fine-tune” neurophysiological properties in animals and potentially downstream behavioral outputs. However, the extreme phenotypes resulting from deletions of adar loci have precluded investigations into the relationship between ADAR levels, target transcripts, and complex behaviors. Here, we engineer Drosophila hypomorphic for ADAR expression using homologous recombination. A substantial reduction in ADAR activity (>80%) leads to altered circadian motor patterns and abnormal male courtship, although surprisingly, general locomotor coordination is spared. The altered phenotypic landscape in our adar hypomorph is paralleled by an unexpected dichotomous response of ADAR target transcripts, i.e. certain adenosines are minimally affected by dramatic ADAR reduction, whereas editing of others is severely curtailed. Furthermore, we use a novel reporter to map RNA editing activity across the nervous system, and we demonstrate that knockdown of editing in fruitless-expressing neurons is sufficient to modify the male courtship song. Our data demonstrate that network-wide temporal and spatial regulation of ADAR activity can tune the complex system of RNA-editing sites and modulate multiple ethologically relevant behavioral modalities.

Double-Stranded RNA Adenosine Deaminase ADAR-1-Induced Hypermutated Genomes among Inactivated Seasonal Influenza and Live Attenuated Measles Virus Vaccines▿

Suspène, Rodolphe; Petit, Vincent; Puyraimond-Zemmour, David; Aynaud, Marie-Ming; Henry, Michel; Guétard, Denise; Rusniok, Christophe; Wain-Hobson, Simon; Vartanian, Jean-Pierre
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.45%
We sought to examine ADAR-1 editing of measles and influenza virus genomes derived from inactivated seasonal influenza and live attenuated measles virus vaccines grown on chicken cells as the culture substrate. Using highly sensitive 3DI-PCR (R. Suspène et al., Nucleic Acids Res. 36:e72, 2008), it was possible to show that ADAR-1 could hyperdeaminate adenosine residues in both measles virus and influenza virus A genomes. Detailed analysis of the dinucleotide editing context showed preferences for 5′ArA and 5′UrA, which is typical of editing in mammalian cells. The hyperedited mutant frequency, including genomes and antigenomes, was a log greater for influenza virus compared to measles virus, suggesting a greater sensitivity to restriction by ADAR-1.

Competition between ADAR and RNAi pathways for an extensive class of RNA targets

Wu, Diane; Lamm, Ayelet T.; Fire, Andrew Z.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 11/09/2011 EN
Relevância na Pesquisa
27.57%
Adenosine deaminases that act on RNAs (ADARs) interact with double-stranded RNAs, deaminating adenosines to inosines. Previous studies of Caenorhabditis elegans suggested an antagonistic interaction between ADAR and RNAi machineries, with ADAR defects suppressed upon additional knockout of RNAi. These results suggest a pool of common RNA substrates capable of engaging both pathways. To define and characterize such substrates, we examined small RNA and mRNA populations of ADAR mutants and identified a distinct set of loci from which RNAi-dependent short RNAs are dramatically upregulated. At these same loci, we observe populations of multiply edited transcripts, supporting a specific role for ADARs in preventing access to the RNAi pathway for an extensive population of dsRNAs. Characterization of these loci reveal an extensive overlap with non-coding and intergenic regions, suggesting that the landscape of ADAR targets may extend beyond previously annotated classes of transcripts.

Solution structure of the N-terminal dsRBD of Drosophila ADAR and interaction studies with RNA

Barraud, Pierre; Heale, Bret S.E.; O’Connell, Mary A.; Allain, Frédéric H.-T.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.57%
Adenosine deaminases that act on RNA (ADAR) catalyze adenosine to inosine (A-to-I) editing in double-stranded RNA (dsRNA) substrates. Inosine is read as guanosine by the translation machinery; therefore A-to-I editing events in coding sequences may result in recoding genetic information. Whereas vertebrates have two catalytically active enzymes, namely ADAR1 and ADAR2, Drosophila has a single ADAR protein (dADAR) related to ADAR2. The structural determinants controlling substrate recognition and editing of a specific adenosine within dsRNA substrates are only partially understood. Here, we report the solution structure of the N-terminal dsRNA binding domain (dsRBD) of dADAR and use NMR chemical shift perturbations to identify the protein surface involved in RNA binding. Additionally, we show that Drosophila ADAR edits the R/G site in the mammalian GluR-2 pre-mRNA which is naturally modified by both ADAR1 and ADAR2. We then constructed a model showing how dADAR dsRBD1 binds to the GluR-2 R/G stem-loop. This model revealed that most side chains interacting with the RNA sugar-phosphate backbone need only small displacement to adapt for dsRNA binding and are thus ready to bind to their dsRNA target. It also predicts that dADAR dsRBD1 would bind to dsRNA with less sequence specificity than dsRBDs of ADAR2. Altogether...

The ADAR protein family

Savva, Yiannis A; Rieder, Leila E; Reenan, Robert A
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Adenosine to inosine (A-to-I) RNA editing is a post-transcriptional process by which adenosines are selectively converted to inosines in double-stranded RNA (dsRNA) substrates. A highly conserved group of enzymes, the adenosine deaminase acting on RNA (ADAR) family, mediates this reaction. All ADARs share a common domain architecture consisting of a variable number of amino-terminal dsRNA binding domains (dsRBDs) and a carboxy-terminal catalytic deaminase domain. ADAR family members are highly expressed in the metazoan nervous system, where these enzymes predominantly localize to the neuronal nucleus. Once in the nucleus, ADARs participate in the modification of specific adenosines in pre-mRNAs of proteins involved in electrical and chemical neurotransmission, including pre-synaptic release machineries, and voltage- and ligand-gated ion channels. Most RNA editing sites in these nervous system targets result in non-synonymous codon changes in functionally important, usually conserved, residues and RNA editing deficiencies in various model organisms bear out a crucial role for ADARs in nervous system function. Mutation or deletion of ADAR genes results in striking phenotypes, including seizure episodes, extreme uncoordination, and neurodegeneration. Not only does the process of RNA editing alter important nervous system peptides...

Adar is essential for optimal presynaptic function

Maldonado, Carolina; Alicea, Daniel; Gonzalez, Maryvi; Bykhovskaia, Maria; Marie, Bruno
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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RNA editing is a powerful way to recode genetic information. Because it potentially affects RNA targets that are predominantly present in neurons, it is widely hypothesized to affect neuronal structure and physiology. Across phyla, loss of the enzyme responsible for RNA editing, Adar, leads to behavioral changes, impaired locomotion, neurodegeneration and death. However, the consequences of a loss of Adar activity on neuronal structure and function have not been studied in detail. In particular, the role of RNA editing on synaptic development and physiology has not been investigated. Here we test the physiological and morphological consequences of the lack of Adar activity on the Drosophila neuromuscular junction (NMJ). Our detailed examination of synaptic transmission showed that loss of Adar increases quantal size, reduces the number of quanta of neurotransmitter released and perturbs the calcium dependence of synaptic release. In addition, we find that staining for several synaptic vesicle proteins is abnormally intense at Adar deficient synapses. Consistent with this finding, Adar mutants showed a major alteration in synaptic ultrastructure. Finally, we present evidence of compensatory changes in muscle membrane properties in response to the changes in presynaptic activity within the Adar mutant NMJs.

Global regulation of alternative splicing by adenosine deaminase acting on RNA (ADAR)

Solomon, Oz; Oren, Shirley; Safran, Michal; Deshet-Unger, Naamit; Akiva, Pinchas; Jacob-Hirsch, Jasmine; Cesarkas, Karen; Kabesa, Reut; Amariglio, Ninette; Unger, Ron; Rechavi, Gideon; Eyal, Eran
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /05/2013 EN
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Using bioinformatics approaches and high-throughput transcriptomic data of ADAR knockdown cells, we globally examined how ADAR and its A-to-I RNA editing activity influence alternative mRNA splicing. Our global analysis reveals that ADAR plays a major role in splicing regulation. Editing sites are enriched in alternatively spliced exons and splicing regulatory elements, but the primary mechanism for ADAR-mediated regulation of alternative splicing is modulation of trans-acting factors involved in the splicing machinery.

ADAR Enzyme and miRNA Story: A Nucleotide that Can Make the Difference

Tomaselli, Sara; Bonamassa, Barbara; Alisi, Anna; Nobili, Valerio; Locatelli, Franco; Gallo, Angela
Fonte: Molecular Diversity Preservation International (MDPI) Publicador: Molecular Diversity Preservation International (MDPI)
Tipo: Artigo de Revista Científica
Publicado em 19/11/2013 EN
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27.57%
Adenosine deaminase acting on RNA (ADAR) enzymes convert adenosine (A) to inosine (I) in double-stranded (ds) RNAs. Since Inosine is read as Guanosine, the biological consequence of ADAR enzyme activity is an A/G conversion within RNA molecules. A-to-I editing events can occur on both coding and non-coding RNAs, including microRNAs (miRNAs), which are small regulatory RNAs of ~20–23 nucleotides that regulate several cell processes by annealing to target mRNAs and inhibiting their translation. Both miRNA precursors and mature miRNAs undergo A-to-I RNA editing, affecting the miRNA maturation process and activity. ADARs can also edit 3′ UTR of mRNAs, further increasing the interplay between mRNA targets and miRNAs. In this review, we provide a general overview of the ADAR enzymes and their mechanisms of action as well as miRNA processing and function. We then review the more recent findings about the impact of ADAR-mediated activity on the miRNA pathway in terms of biogenesis, target recognition, and gene expression regulation.

The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster

Li, Xianghua; Overton, Ian M.; Baines, Richard A.; Keegan, Liam P.; O’Connell, Mary A.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
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RNA editing by deamination of specific adenosine bases to inosines during pre-mRNA processing generates edited isoforms of proteins. Recoding RNA editing is more widespread in Drosophila than in vertebrates. Editing levels rise strongly at metamorphosis, and Adar5G1 null mutant flies lack editing events in hundreds of CNS transcripts; mutant flies have reduced viability, severely defective locomotion and age-dependent neurodegeneration. On the other hand, overexpressing an adult dADAR isoform with high enzymatic activity ubiquitously during larval and pupal stages is lethal. Advantage was taken of this to screen for genetic modifiers; Adar overexpression lethality is rescued by reduced dosage of the Rdl (Resistant to dieldrin), gene encoding a subunit of inhibitory GABA receptors. Reduced dosage of the Gad1 gene encoding the GABA synthetase also rescues Adar overexpression lethality. Drosophila Adar5G1 mutant phenotypes are ameliorated by feeding GABA modulators. We demonstrate that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar5G1 null mutant or targeted Adar knockdown motor neurons exhibit increased excitability. GABA inhibitory signalling is impaired in human epileptic and autistic conditions...

ADAR Regulates RNA Editing, Transcript Stability, and Gene Expression

Wang, Isabel X.; So, Elizabeth; Devlin, James L.; Zhao, Yue; Wu, Ming; Cheung, Vivian G.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.57%
Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine, which is then recognized as guanosine. To study the role of ADAR proteins in RNA editing and gene regulation, we sequenced and compared the DNA and RNA of human B cells. Then, we followed up the findings experimentally with siRNA knockdown and RNA and protein immunoprecipitations. The results uncovered over 60,000 A-to-G editing sites and several thousand genes whose expression levels are influenced by ADARs. Of these ADAR targets, 90% were identified. Our results also reveal that ADAR regulates transcript stability and gene expression through interaction with HuR (ELAVL1). These findings extend the role of ADAR and show that it cooperates with other RNA-processing proteins to regulate the sequence and expression of transcripts in human cells.

ADAR mediates differential expression of polycistronic microRNAs

Chawla, Geetanjali; Sokol, Nicholas S.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Adenosine deaminases acting on RNAs (ADARs) convert adenosine residues to inosines in primary microRNA (pri-miRNA) transcripts to alter the structural conformation of these precursors and the subsequent functions of the encoded microRNAs (miRNAs). Here we show that RNA editing by Drosophila ADAR modulates the expression of three co-transcribed miRNAs encoded by the evolutionarily conserved let-7-Complex (let-7-C) locus. For example, a single A-to-I change at the −6 residue of pri-miR-100, the first miRNA in this let-7-C polycistronic transcript, leads to enhanced miRNA processing by Drosha and consequently enhanced functional miR-100 both in vitro as well as in vivo. In contrast, other editing events, including one at the +43 residue of the pri-miR-125, destabilize the primary transcript and reduce the levels of all three encoded miRNAs. Consequently, loss of adar in vivo leads to reduced miR-100 but increased miR-125. In wild-type animals, the destabilizing editing events in pri-let-7-C increase during the larval-to-adult transition and are critical for the normal downregulation of all three miRNAs seen late in metamorphosis. These findings unravel a new regulatory role for ADAR and raise the possibility that ADAR mediates the differential expression characteristic of many polycistronic miRNA clusters.

Hyperediting of human T-cell leukemia virus type 2 and simian T-cell leukemia virus type 3 by the dsRNA adenosine deaminase ADAR-1

Ko, Nga Ling; Birlouez, Emmanuel; Wain-Hobson, Simon; Mahieux, Renaud; Vartanian, Jean-Pierre
Fonte: Society for General Microbiology Publicador: Society for General Microbiology
Tipo: Artigo de Revista Científica
Publicado em /12/2012 EN
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RNA editing mediated by adenosine deaminases acting on RNA (ADARs) converts adenosine (A) to inosine (I) residues in dsRNA templates. While ADAR-1-mediated editing was essentially described for RNA viruses, the present work addresses the issue for two δ-retroviruses, human T-cell leukemia virus type 2 and simian T-cell leukemia virus type 3 (HTLV-2 and STLV-3). We examined whether ADAR-1 could edit HTLV-2 and STLV-3 virus genomes in cell culture and in vivo. Using a highly sensitive PCR-based method, referred to as 3DI-PCR, we showed that ADAR-1 could hypermutate adenosine residues in HTLV-2. STLV-3 hypermutation was obtained without using 3DI-PCR, suggesting a higher mutation frequency for this virus. Detailed analysis of the dinucleotide editing context showed preferences for 5′ ArA and 5′ UrA. In conclusion, the present observations demonstrate that ADAR-1 massively edits HTLV-2 and STLV-3 retroviruses in vitro, but probably remains a rare phenomenon in vivo.

Aspectos ambientais e sociais da ocupa????o irregular do loteamento Quer??ncia III, da cidade do Rio Grande, RS, Brasil

Noguez, Cristiane Teixeira; Hartmann, Carlos
Fonte: Universidade Federal do Rio Grande Publicador: Universidade Federal do Rio Grande
Tipo: Artigo de Revista Científica
POR
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Ocupa????es irregulares em ??reas inadequadas s??o comuns na grande maioria das cidades brasileiras. Normalmente sem qualquer infra-estrutura, s??o procuradas para resolver os problemas da popula????o de baixa renda, constituindo um problema social. Dados capturados por sensor digital de pequeno formato s??o ideais pela facilidade de manipula????o e baixo custo, com alta resolu????o espacial. Este trabalho mostra a utilidade do sistema ADAR 1000 nas condi????es atuais do loteamento irregular Quer??ncia III, localizado perto de linha de costa (dunas frontais) da cidade de Rio Grande, RS.; Ilegal divisions into lots in inappropriate areas are common in the great majority of the Brazilian cities. Usually without any infrastructure, them search to solve the problems of the population of low income, to constitute a social problem given captured for sensor digital of small format they are ideal, for the handling easiness and low cost with high space resolution. This work shows the usefulness of the system ADAR 1000 in the rising of the current conditions of the division into lots Querencia located III close to coast line (front dunes) of the city of Rio Grande,RS.

Uso de imagens de pequeno formato como instrumento na elabora????o e implanta????o de projetos costeiros. O sistema ADAR 1000

Cunha, Rosa Maria Piccoli da; Bulla, Luiz Angelo Sobreiro; Hartmann, Carlos
Fonte: Universidade Federal do Rio Grande Publicador: Universidade Federal do Rio Grande
Tipo: Artigo de Revista Científica
POR
Relevância na Pesquisa
27.57%
Apesar de existirem sistemas orbitais de alta defini????o, imagens capturadas por sensores aerotransportados, s??o muito utilizadas, pela sua versatilidade, alta defini????o, disponibilidade em tempo real, proporcionando alto custo-beneficio. As aerofotos s??o as mais indicadas para certos tipos de levantamentos, quando se leva em considera????o, facilidade de obten????o, capacidade de tratamento digital, cobertura de nuvens e possibilidade de realiza????o de novos levantamentos na escala pretendida em tempo real. As fotografias a??reas de pequeno formato s??o uma alternativa na identifica????o de ??reas de preserva????o permanente ?? utiliza????o de cenas de alta resolu????o espacial obtidas a partir de sensores orbitais. S??o muito eficientes na identifica????o de ??reas de preserva????o permanentes e de ??reas antr??picas, fornecendo informa????es com grande riqueza de detalhes, compar??veis e mesmo superiores aos sensores de sat??lites de alta resolu????o. No Brasil este tipo de dado tem sido utilizado com frequ??ncia, destacando-se seu uso no mapeamento em detalhe de fei????es f??sicas da linha de costa e zona costeira. Apesar de certa reserva, j?? est?? provado que as c??meras digitais n??o m??tricas e de pequeno formato tem real potencial para uso em levantamentos aerofotogram??tricos. Para esta finalidade existem sistemas especialmente constru??dos para tal fim...

Registro de imagens 35 mm (Sistema ADAR 1000) utilizando alvos in loco e DGPS

Hartmann, Carlos; Souza, Suzane Rabelo
Fonte: Universidade Federal do Rio Grande Publicador: Universidade Federal do Rio Grande
Tipo: Artigo de Revista Científica
POR
Relevância na Pesquisa
27.57%
O uso de imagens de pequeno e médio formato tem se intensificado nos últimos anos em todo o mundo e particularmente na região da palnície Costeira (RS) em função da disponibilidade do sistema ADAR 1000. O uso destas imagens em detrimento das imagens de satélite de alta definição está na facilidade de aquisição, tornando seu usuário independente, realizando a aquisição dos dados quando necessitar, com a definição e resolução que resolverá seu problema. O sistema ADAR captura as imagens ao longo da linha de vôo com um GPS próprio, adquirindo Pontos de Controle (PC) em tempo real, o que permite a localização da imagem em cartas e/ou mapas sendo de difícil integração num Sistema de Informações Geográficas. Entretanto, o registro da imagem no terreno, necessita de outros pontos de controle visualizados na imagem e no terreno, distribuídos ao longo da mesma. Neste sentido, se a área a ser estudada for urbana, é possível visualizar inúmeros PC em função dos alvos e estruturas disponíveis da malha urbana, ou seja, esquinas, muros, cruzamento de ruas, meio fio, etc., entretanto no caso de imagens obtidas em áreas rurais, devido a inexistência de estruturas que possam ser utilizadas como PC, existe a necessidade de utilizar alvos artificiais...

Tuning of RNA editing by ADAR is required in Drosophila

Keegan, Liam P; Brindle, James; Gallo, Angela; Leroy, Anne; Reenan, Robert A; O'Connell, Mary A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.72%
RNA editing increases during development in more than 20 transcripts encoding proteins involved in rapid synaptic neurotransmission in Drosophila central nervous system and muscle. Adar (adenosine deaminase acting on RNA) mutant flies expressing only genome-encoded, unedited isoforms of ion-channel subunits are viable but show severe locomotion defects. The Adar transcript itself is edited in adult wild-type flies to generate an isoform with a serine to glycine substitution close to the ADAR active site. We show that editing restricts ADAR function since the edited isoform of ADAR is less active in vitro and in vivo than the genome-encoded, unedited isoform. Ubiquitous expression in embryos and larvae of an Adar transcript that is resistant to editing is lethal. Expression of this transcript in embryonic muscle is also lethal, with above-normal, adult-like levels of editing at sites in a transcript encoding a muscle voltage-gated calcium channel.

Fmrp Interacts with Adar and Regulates RNA Editing, Synaptic Density and Locomotor Activity in Zebrafish

Shamay-Ramot, Adi; Khermesh, Khen; Porath, Hagit T.; Barak, Michal; Pinto, Yishay; Wachtel, Chaim; Zilberberg, Alona; Lerer-Goldshtein, Tali; Efroni, Sol; Levanon, Erez Y.; Appelbaum, Lior
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 04/12/2015 EN
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Fragile X syndrome (FXS) is the most frequent inherited form of mental retardation. The cause for this X-linked disorder is the silencing of the fragile X mental retardation 1 (fmr1) gene and the absence of the fragile X mental retardation protein (Fmrp). The RNA-binding protein Fmrp represses protein translation, particularly in synapses. In Drosophila, Fmrp interacts with the adenosine deaminase acting on RNA (Adar) enzymes. Adar enzymes convert adenosine to inosine (A-to-I) and modify the sequence of RNA transcripts. Utilizing the fmr1 zebrafish mutant (fmr1-/-), we studied Fmrp-dependent neuronal circuit formation, behavior, and Adar-mediated RNA editing. By combining behavior analyses and live imaging of single axons and synapses, we showed hyperlocomotor activity, as well as increased axonal branching and synaptic density, in fmr1-/- larvae. We identified thousands of clustered RNA editing sites in the zebrafish transcriptome and showed that Fmrp biochemically interacts with the Adar2a protein. The expression levels of the adar genes and Adar2 protein increased in fmr1-/- zebrafish. Microfluidic-based multiplex PCR coupled with deep sequencing showed a mild increase in A-to-I RNA editing levels in evolutionarily conserved neuronal and synaptic Adar-targets in fmr1-/- larvae. These findings suggest that loss of Fmrp results in increased Adar-mediated RNA editing activity on target-specific RNAs...