RADAR: a rigorously annotated database of A-to-I RNA editing

Ramaswami, Gokul; Li, Jin Billy

doi:10.1093/nar/gkt996

Cited by 459 publications

(515 citation statements)

References 34 publications

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“…However, such highly specific A-to-I editing events within exonic ORF sequences are the exception in the context of present understanding. Of the several thousand A-to-I-editing sites identified through next generation sequencing studies, the vast majority is found within noncoding sequences of genes that are not inducible by IFN (56,(73)(74)(75)(76)(77)(78). What then is the molecular basis of the IFN-induced, dsRNA-dependent innate responses exemplified by eIF2␣ phosphorylation and SG formation that we now find are suppressed by A-to-I editing but are de-repressed in the absence of ADAR1 following IFN treatment?…”

Section: Discussionmentioning

confidence: 99%

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

George

Ramaswami

et al. 2016

Journal of Biological Chemistry

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One mechanism by which cells respond to different forms of stress is the global reduction of protein synthesis (1). Phosphorylation of protein synthesis initiation factor eIF2␣ on serine 51 is recognized as a universal mechanism of translation suppression in response to cellular stress (1, 2). Four different protein kinases are activated in mammalian cells in response to different stresses, and they all catalyze Ser-51 phosphorylation of eIF2␣ as follows: protein kinase regulated by RNA (PKR) activated by double-stranded RNA; heme-regulated inhibitor kinase activated by hemin deficiency and oxidative stress; general control non-derepressible kinase 2 (GCN2) activated by amino acid deficiency; and PKR-like endoplasmic reticulum kinase activated by protein misfolding and endoplasmic reticulum stress (2, 3). The global inhibition of translation in cultured cells mediated by eIF2␣ phosphorylation is linked to the formation of stress granules (SG), 2 cytoplasmic aggregates of stalled 40S ribosomal subunit-containing translation initiation complexes, translation initiation factors, and RNA-binding proteins, including Ras GTPase-activating protein-Src homology 3 domain binding protein 1 G3BP1 (4). Stress granule formation is one hallmark of virus infection, serving as an index of innate immune responses, and is PKR-dependent for a variety of viruses (5-8).A cornerstone of innate antiviral immunity is the interferon (IFN) system (9, 10). IFNs act through the transcriptional induction of IFN-stimulated genes that encode products responsible for the biological activities of IFNs, including the ability of IFNs to inhibit virus multiplication and enhance apoptosis (11-13). Among the IFN-stimulated gene products is the PKR kinase induced by IFN through canonical JAK-STAT signaling (14 -16). PKR is activated by binding dsRNA that mediates PKR dimerization and autophosphorylation; activated PKR catalyzes the phosphorylation of eIF2␣ (17)(18)(19)(20). In the case of several viruses, PKR displays antiviral and proapoptotic activities (12,21,22). Exemplified by measles virus, PKR sufficiency and kinase activation correlate with reduced virus growth (23, 24), enhanced induction of IFN␤ (25,26), increased SG responses (7), and increased cytotoxicity and apoptosis (27,28). The central importance of PKR furthermore is illustrated both by the large number of viruses that encode gene products that antagonize PKR activation and function, and by the effects of genetic disruption of the Pkr gene (12,13,29).Similar to PKR, ADAR1 (adenosine deaminase acting on RNA1) is an IFN-inducible dsRNA-binding protein with enzyme activity (30, 31). However, unlike PKR, ADAR1 uses dsRNA as a substrate (32). ADAR1 catalyzes the C6 deamination of adenosine (A) in dsRNA structures to generate inosine (I), a process known as A-to-I editing (33,34) samuel@lifesci.ucsb.edu.2 The abbreviations used are: SG, stress granule; ADAR1, adenosine deaminase acting on RNA1; MEF, mouse embryo fibroblast; mmPCR-seq, microfluidics-based multiplex PCR and deep sequencing;...

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Section: Discussionmentioning

confidence: 99%

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

George

Ramaswami

et al. 2016

Journal of Biological Chemistry

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123

101

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“…In the absence of a whole-genome data set, we explored RNA editing profiles per cell comparing RNA-seq data with a comprehensive and nonredundant collection of known events, including A-to-I changes from our catalog (Picardi et al 2015) as well as sites annotated in the RADAR database (Ramaswami and Li 2014). In all, we interrogated more than 4.5 million positions per cell using our REDItools suite.…”

Section: Rna Editing Calling and Data Analysismentioning

confidence: 99%

Single-cell transcriptomics reveals specific RNA editing signatures in the human brain

Picardi

Horner

Pesole

2017

RNA

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While RNA editing by A-to-I deamination is a requisite for neuronal function in humans, it is under-investigated in single cells. Here we fill this gap by analyzing RNA editing profiles of single cells from the brain cortex of living human subjects. We show that RNA editing levels per cell are bimodally distributed and distinguish between major brain cell types, thus providing new insights into neuronal dynamics.

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“…For example, two messages encoding voltage-dependent potassium channels in Doryteuthis pealeii and Doryteuthis opalescens (formerly known as Loligo pealeii and Loligo opalescens) exhibited over 30 individual recoding sites (Patton et al, 1997;Rosenthal and Bezanilla, 2002). Subsequent studies on mRNAs encoding other ion channels, ion pumps and ADARs in squid revealed as many recoding editing sites in these few messages as had been identified in the entire human transcriptome (Colina et al, 2010;Liu et al, 2001;Palavicini et al, 2009;Pinto et al, 2014;Ramaswami and Li, 2014;Ramaswami et al, 2013;Rosenthal et al, 1997). It seemed unlikely that the squid studies happened upon highly edited messages by chance.…”

Section: Cephalopod Rna Editing Breaks the Rulesmentioning

confidence: 99%

The emerging role of RNA editing in plasticity

Rosenthal¹

2015

Journal of Experimental Biology

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All true metazoans modify their RNAs by converting specific adenosine residues to inosine. Because inosine binds to cytosine, it is a biological mimic for guanosine. This subtle change, termed RNA editing, can have diverse effects on various RNA-mediated cellular pathways, including RNA interference, innate immunity, retrotransposon defense and messenger RNA recoding. Because RNA editing can be regulated, it is an ideal tool for increasing genetic diversity, adaptation and environmental acclimation. This review will cover the following themes related to RNA editing: (1) how it is used to modify different cellular RNAs, (2) how frequently it is used by different organisms to recode mRNA, (3) how specific recoding events regulate protein function, (4) how it is used in adaptation and (5) emerging evidence that it can be used for acclimation. Organismal biologists with an interest in adaptation and acclimation, but with little knowledge of RNA editing, are the intended audience.

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RADAR: a rigorously annotated database of A-to-I RNA editing

Cited by 459 publications

References 34 publications

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

Single-cell transcriptomics reveals specific RNA editing signatures in the human brain

The emerging role of RNA editing in plasticity

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