Accurate identification of human Alu and non-Alu RNA editing sites

Ramaswami, Gokul; Lin, Wei; Piskol, Robert; Tan, Meng How; Davis, Carrie A.; Li, Jin Billy

doi:10.1038/nmeth.1982

Cited by 328 publications

(478 citation statements)

References 21 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 support of the former possibility, DARNED (50), a database compiling RNA editing sites from multiple publications, reports that transcripts of Spi1 (a gene encoding PU.1; chromosome 11, start: 47379732, end: 47400127) showed evidence of A-to-I RNA editing at 28 sites (14). Future geneexpression analyses and identification of de novo RNA editing sites through analysis of whole-genome and transcriptome DNA-RNA differences (15) in normal HSC harboring enforced ADAR1 p150 expression and LSC will be necessary to dissect further the link between ADAR1 activation PU.1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, previous studies reveal extensive RNA editing in the human transcriptome (14)(15)(16)(17), primarily in primate-specific Alu sequences (18)(19)(20), which promotes splice isoform diversity. RNA editing activity is mediated by the adenosine deaminase acting on dsRNA (ADAR) family of editases (21), which includes ADAR1 (also known as ADAR), ADAR2 (ADARB1), and ADAR3 (ADARB2).…”

mentioning

confidence: 99%

ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

Jiang

Crews

Barrett

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

150

188

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The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, wholetranscriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU.1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.

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“…A-to-I editing events occur more frequently in noncoding sequences including repetitive elements and small RNA precursors. Alu and LINE elements, when positioned as sense and antisense pairs nearby one another in the genome, exhibit the potential to form long dsRNAs, and these dsRNAs can be hyper-edited at multiple adenosines [8][9][10]. Several studies suggest that the hyper-editing in repetitive elements is involved in the regulation of gene expression [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner

et al. 2015

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Adenosine deaminases acting on RNA (ADARs) are involved in adenosine-to-inosine RNA editing and are implicated in development and diseases. Here we observed that ADAR1 deficiency in human embryonic stem cells (hESCs) significantly affected hESC differentiation and neural induction with widespread changes in mRNA and miRNA expression, including upregulation of self-renewal-related miRNAs, such as miR302s. Global editing analyses revealed that ADAR1 editing activity contributes little to the altered miRNA/mRNA expression in ADAR1-deficient hESCs upon neural induction. Genome-wide iCLIP studies identified that ADAR1 binds directly to pri-miRNAs to interfere with miRNA processing by acting as an RNA-binding protein. Importantly, aberrant expression of miRNAs and phenotypes observed in ADAR1-depleted hESCs upon neural differentiation could be reversed by an enzymatically inactive ADAR1 mutant, but not by the RNA-binding-null ADAR1 mutant. These findings reveal that ADAR1, but not its editing activity, is critical for hESC differentiation and neural induction by regulating miRNA biogenesis via direct RNA interaction.

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Accurate identification of human Alu and non-Alu RNA editing sites

Cited by 328 publications

References 21 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

ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner

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