Elevated activity of the large form of ADAR1 in vivo: Very efficient RNA editing occurs in the cytoplasm

Wong, Sharon; Sato, Shuji; Lazinski, David W.

doi:10.1261/rna.5160403

Cited by 40 publications

(53 citation statements)

References 35 publications

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“…These data suggest that ADAR1-mediated RNA editing occurs in different cellular organelles. Elevated activity of the long form of ADAR1 in vivo could result in highly efficient RNA editing in the cytoplasm (46), supporting the hypothesis that ADAR1-mediated RNA editing occurs in the cytoplasm in addition to the nucleus. Finally, the nucleolar localization of ADAR1 suggests a role for RNA editing in nucleolar function.…”

Section: Intracellular Distribution Of Adar1 Isoforms Is Regulated Thsupporting

confidence: 56%

Subcellular Distribution of ADAR1 Isoforms Is Synergistically Determined by Three Nuclear Discrimination Signals and a Regulatory Motif

Nie¹,

Zhao²,

et al. 2004

Journal of Biological Chemistry

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ADAR1 is an RNA-specific adenosine deaminase that edits RNA sequences. We have demonstrated previously that different ADAR1 isoforms are induced during acute inflammation. Here we show that the mouse ADAR1 isoforms are differentially localized in cellular compartments and that their localization is controlled by several independent signals. Nuclear import of the full-length ADAR1 is predominantly regulated by a nuclear localization signal at the C terminus (NLS-c), which consists of a bipartite basic amino acid motif plus the last 39 residues of ADAR1. Deletion of the NLS-c causes the truncated ADAR1 protein to be retained in the cytoplasm. The addition of this sequence to pyruvate kinase causes the cytoplasmic protein to be localized within the nucleus. The localization of nuclear ADAR1 is determined by a dynamic balance between the nucleolar binding activity of the nucleolar localization signal (NoLS) in the middle of the protein and the exporting activity of the nuclear exporter signal (NES) near the N terminus. The NoLS consists of a typical monopartite cluster of basic residues followed by the third doublestranded RNA-binding domain. These signals act independently; however, NES function can be completely silenced by the NLS-c when a regulatory motif within the catalytic domain and the NoLS are deleted. Thus, the intracellular distribution of the various ADAR1 isoforms is determined by NLS-c, NES, NoLS, and a regulatory motif.

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Section: Intracellular Distribution Of Adar1 Isoforms Is Regulated Thsupporting

confidence: 56%

Subcellular Distribution of ADAR1 Isoforms Is Synergistically Determined by Three Nuclear Discrimination Signals and a Regulatory Motif

Nie¹,

Zhao²,

et al. 2004

Journal of Biological Chemistry

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“…2A; Sato et al 2001;Wong et al 2001Wong et al , 2003Wong and Lazinski 2002;Desterro et al 2003). Using similar vector constructs, we here show that the observation is not a translational phenomenon but originates from a heterologous splicing event between a vectorencoded 59-splice site (SV40 intron) and the previously unknown 39-splice site of the intron in exon 2 of ADAR1 (Fig.…”

Section: Alternatively Spliced Adar1-a Is Translated But Evades Nmdmentioning

confidence: 57%

“…It has been observed in several studies that two protein species corresponding to iADAR1 and cADAR1 appear when overexpressing iADAR1 from different vector constructs Wong et al 2001Wong et al , 2003Wong and Lazinski 2002;Desterro et al 2003).…”

Section: Identification Of a Novel Intron In Adar1mentioning

confidence: 99%

“…Accordingly, the shorter form is not detected by an anti-HA antibody, which recognizes the amino-terminal HA epitope (data not shown). Lazinski and coworkers have previously reported that internal deletions in the unique amino terminus of iADAR1 prevented the additional translation of cADAR1 (Wong et al 2003). We therefore made a series of constructs with deletions in the amino-terminal part of iADAR1 and analyzed the expressed proteins by Western blotting using an anti-Flag antibody ( Fig.…”

Section: Identification Of a Novel Intron In Adar1mentioning

confidence: 99%

See 1 more Smart Citation

Alternative splicing of the ADAR1 transcript in a region that functions either as a 5′-UTR or an ORF

Lykke‐Andersen¹,

Piñol-Roma²,

Kjems³

2007

RNA

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The ADAR enzymes mediate the hydrolytic deamination of adenosines in specific RNA substrates and thereby diversify both the transcriptome and the proteome in metazoan species. Three promoters drive the transcription from the ADAR1 gene yielding the ADAR1-A, -B, and -C transcripts, which, in turn, lead to the production of two protein isoforms, namely, iADAR1 and cADAR1. In this study, we establish the presence of a previously unidentified alternative intron within the 59-end of the common second exon of mRNAs encoding ADAR1 in primate species-a region that can function either as a 59-UTR or an ORF. In addition, it is shown that the relative expression of the three promoter-specific ADAR1 transcripts is tissue specific and that the novel intron is excised from all transcripts, but at different relative levels indicating a specific regulation of the alternative splicing. Finally, possible functional consequences of the splicing are investigated. From these studies, we conclude that the alternatively spliced ADAR1-A transcript is immune to nonsense-mediated decay although it is a potential substrate. Moreover, this transcript is associated with translating ribosomes, which suggests that a truncated version of iADAR1 is expressed.

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“…In vitrotranscribed, gel-purified mP-SF and mE-SF RNAs were incubated with nuclear extract obtained from cells transfected with an ADAR1 expression vector (Wong et al 2003), and the extent of editing at the amber/W site was determined using a previously described RT-PCR and Sty I digestion assay (Linnstaedt et al 2006). We observed that mP-SF RNA was edited threefold more efficiently than mE-SF RNA (Fig.…”

Section: The Branched Structures Of Two Hdv-3 Isolates Are Edited Witmentioning

confidence: 92%

The fraction of RNA that folds into the correct branched secondary structure determines hepatitis delta virus type 3 RNA editing levels

Linnstaedt

Kasprzak²,

Shapiro

et al. 2009

RNA

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RNA editing by the host RNA adenosine deaminase ADAR1 at the amber/W site of hepatitis delta virus RNA plays a central role in the viral replication cycle by affecting the balance between viral RNA synthesis and packaging. Previously, we found that HDV genotype III (HDV-3) RNA can form two secondary structures following transcription: an unbranched rod structure, which is characteristic of HDV, and a metastable branched structure that serves as the substrate for editing. The unstable nature of the branched editing substrate structure raised the possibility that structural dynamics of the RNA following transcription could determine the rate at which editing occurs. Here, editing and its control are examined in two HDV-3 isolates, from Peru and Ecuador. Analysis of editing in vitro by ADAR1 indicated that the branched structure formed by RNA derived from the Peruvian isolate is edited more efficiently than that from the Ecuadorian isolate. In contrast, in the context of replication, Peruvian RNA is edited less efficiently than RNA containing Ecuadorian sequences. Computational analyses of RNA folding using the massively parallel genetic algorithm (MPGAfold) indicated that the Peruvian RNA is less likely to form the branched structure required for editing than the Ecuadorian isolate. This difference was confirmed by in vitro transcription of these RNAs. Overall, our data indicate that HDV-3 controls RNA editing levels via (1) the fraction of the RNA that folds, during transcription, into the metastable branched structure required for editing and (2) the efficiency with which ADAR1 edits this branched substrate RNA.

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Elevated activity of the large form of ADAR1 in vivo: Very efficient RNA editing occurs in the cytoplasm

Cited by 40 publications

References 35 publications

Subcellular Distribution of ADAR1 Isoforms Is Synergistically Determined by Three Nuclear Discrimination Signals and a Regulatory Motif

Subcellular Distribution of ADAR1 Isoforms Is Synergistically Determined by Three Nuclear Discrimination Signals and a Regulatory Motif

Alternative splicing of the ADAR1 transcript in a region that functions either as a 5′-UTR or an ORF

The fraction of RNA that folds into the correct branched secondary structure determines hepatitis delta virus type 3 RNA editing levels

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