An RNA Editor, Adenosine Deaminase Acting on Double-Stranded RNA (ADAR1)

George, Cyril X.; John, Lijo; Samuel, Charles E.

doi:10.1089/jir.2014.0001

Cited by 62 publications

(65 citation statements)

References 107 publications

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“…Interestingly, we found that ADAR1 in hESCs was predominately localized to the nucleus (data not shown) as previously reported [49]. Consistent with its nuclear localization, ADAR1 interacted with endogenous DGCR8 (Figure 5B), but its interaction with DICER was barely detectable under our experimental conditions.…”

Section: Adar1 Acts As An Rna-binding Protein That Directly Inhibits supporting

confidence: 90%

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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Section: Adar1 Acts As An Rna-binding Protein That Directly Inhibits supporting

confidence: 90%

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

et al. 2015

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“…We identified several DI-RNA sequences bearing clusters of A-to-G or U-to-C mutations and show through a computational approach that the sequences flanking the edited nucleotides, as well as the average editing frequency, were characteristic of ADAR1, but not ADAR2 (21). Of the three known ADARs, only the IFN-inducible ADAR1 isoform (also called p150) is cytoplasmic (58,59) and localizes to stress granules (56). These granules are induced during MV-C KO infection and form in close proximity to viral replication sites (14).…”

Section: Discussionmentioning

confidence: 99%

Measles Virus Defective Interfering RNAs Are Generated Frequently and Early in the Absence of C Protein and Can Be Destabilized by Adenosine Deaminase Acting on RNA-1-Like Hypermutations

Pfaller

Mastorakos

Matchett

et al. 2015

J Virol

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Defective interfering RNAs (DI-RNAs) of the viral genome can form during infections of negative-strand RNA viruses and outgrow full-length viral genomes, thereby modulating the severity and duration of infection. Here we document the frequent de novo generation of copy-back DI-RNAs from independent rescue events both for a vaccine measles virus (vac2) and for a wildtype measles virus (IC323) as early as passage 1 after virus rescue. Moreover, vaccine and wild-type C-protein-deficient (C-protein-knockout [C KO ]) measles viruses generated about 10 times more DI-RNAs than parental virus, suggesting that C enhances the processivity of the viral polymerase. We obtained the nucleotide sequences of 65 individual DI-RNAs, identified breakpoints and reinitiation sites, and predicted their structural features. Several DI-RNAs possessed clusters of A-to-G or U-to-C transitions. Sequences flanking these mutation sites were characteristic of those favored by adenosine deaminase acting on RNA-1 (ADAR1), which catalyzes in double-stranded RNA the C-6 deamination of adenosine to produce inosine, which is recognized as guanosine, a process known as A-to-I RNA editing. In individual DI-RNAs the transitions were of the same type and occurred on both sides of the breakpoint. These patterns of mutations suggest that ADAR1 edits unencapsidated DI-RNAs that form doublestrand RNA structures. Encapsidated DI-RNAs were incorporated into virus particles, which reduced the infectivity of virus stocks. The C KO phenotype was dominant: DI-RNAs derived from vac2 with a C KO suppressed the replication of vac2, as shown by coinfections of interferon-incompetent lymphatic cells with viruses expressing different fluorescent reporter proteins. In contrast, coinfection with a C-protein-expressing virus did not counteract the suppressive phenotype of DI-RNAs. IMPORTANCE Recombinant measles viruses (MVs) are in clinical trials as cancer therapeutics and as vectored vaccines for HIV-AIDS and other infectious diseases. The efficacy of MV-based vectors depends on their replication proficiency and immune activation capacity.Here we document that copy-back defective interfering RNAs (DI-RNAs) are generated by recombinant vaccine and wild-type MVs immediately after rescue. The MV C protein interferes with DI-RNA generation and may enhance the processivity of the viral polymerase. We frequently detected clusters of A-to-G or U-to-C transitions and noted that sequences flanking individual mutations contain motifs favoring recognition by the adenosine deaminase acting on RNA-1 (ADAR1). The consistent type of transitions on the DI-RNAs indicates that these are direct substrates for editing by ADAR1. The ADAR1-mediated biased hypermutation events are consistent with the protein kinase R (PKR)-ADAR1 balancing model of innate immunity activation. We show by coinfection that the C-defective phenotype is dominant.

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“…So far, many ADAR1 homologous sequences have been cloned and reported in vertebrates and invertebrates (George et al, 2014;Lynch, 2004;Mannion et al, 2014). ADAR1 is an IFN-induced gene involved in antivirus activity (Gelinas et al, 2011;Mangeat et al, 2012;Wu et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Genome organization and transcriptional regulation of Adenosine Deaminase Acting on RNA gene 1 (ADAR1) in grass carp (Ctenopharyngodon idella)

Sun

Wang

Liu

et al. 2015

Developmental & Comparative Immunology

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An RNA Editor, Adenosine Deaminase Acting on Double-Stranded RNA (ADAR1)

Cited by 62 publications

References 107 publications

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

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

Measles Virus Defective Interfering RNAs Are Generated Frequently and Early in the Absence of C Protein and Can Be Destabilized by Adenosine Deaminase Acting on RNA-1-Like Hypermutations

Genome organization and transcriptional regulation of Adenosine Deaminase Acting on RNA gene 1 (ADAR1) in grass carp (Ctenopharyngodon idella)

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