Affinage

ADARB1

Double-stranded RNA-specific editase 1 · UniProt P78563

Length
741 aa
Mass
80.8 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADARB1 (ADAR2) is a nuclear RNA-editing enzyme that site-selectively deaminates adenosine to inosine within double-stranded regions of pre-mRNA and miRNA precursors, with the GluA2 (GluR-B) Q/R site as its physiologically critical substrate—loss of this single editing event causes fatal seizures, and engineering the edited codon directly into GluA2 alleles fully rescues the ADAR2-null lethal phenotype (PMID:10894545). In motor neurons, ADAR2 deficiency drives a progressive ALS-like degeneration that is likewise entirely attributable to Q/R-unedited GluA2 (PMID:20826656), and CREB-driven ADAR2 upregulation protects ischemia-vulnerable hippocampal neurons through restored Q/R editing (PMID:16504947). Catalysis is performed by a deaminase domain that coordinates an active-site zinc and a buried inositol hexakisphosphate cofactor required for activity (PMID:16141067), and that recognizes its target adenosine by flipping it out of the duplex into the active site (PMID:27065196, PMID:11015203). Substrate selectivity is set jointly by RNA features—nearest-neighbor sequence preferences and the identity of the base opposing the editing adenosine (PMID:11041852, PMID:11421361)—and by tandem dsRNA-binding motifs that achieve structure- and sequence-specific readout of substrate stem-loops through the minor groove (PMID:20946981, PMID:16472753); these same dsRBMs mediate dimerization and ternary-complex formation on the RNA that is rate-limiting for efficient editing (PMID:16682559, PMID:12163487). Editing output is heavily regulated: ADAR2 sequesters itself in the nucleolus via rRNA binding, limiting access to nucleoplasmic substrates (PMID:14612560), and it autoedits its own pre-mRNA to create an alternative splice site that lowers its expression in a negative-feedback loop (PMID:16382140, PMID:14660658). Its nuclear localization and stability are controlled by Pin1 and the E3 ligase WWP2, with PKCζ and JNK1 providing kinase input and SRSF9, RPS14, and the MBII-52 snoRNA acting as substrate-specific repressors (PMID:21847096, PMID:29694894, PMID:23139803, PMID:29992293, PMID:23275536, PMID:15939761). Beyond neuronal physiology, ADAR2 editing rebalances the miRNA landscape and acts as a tumor suppressor in glioma (PMID:25582055, PMID:22525274), contributes to circadian gene-expression rhythmicity under CLOCK-BMAL1 control (PMID:27893733), and supports glucose-stimulated insulin secretion and endothelial immune-cell trafficking (PMID:20501795, PMID:37100060). Biallelic loss-of-function variants in ADARB1 cause microcephaly, intellectual disability, and epileptic encephalopathy in humans (PMID:32220291).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2000 High

    Established which substrate of this broad-specificity editase actually matters for life, resolving whether the lethal phenotype reflected global editing loss or one critical site.

    Evidence ADAR2-null mice with knock-in rescue using pre-edited GluA2 alleles (genetic epistasis)

    PMID:10894545

    Open questions at the time
    • Does not explain the function of the dozens of other edited sites lost in the knockout
    • Mechanism of seizure death beyond GluA2 Ca2+ permeability not dissected
  2. 2000 High

    Defined the biochemical determinants of editing-site selection, showing selectivity is dictated largely by RNA substrate features rather than enzyme identity.

    Evidence In vitro deamination assays comparing ADAR1 and ADAR2 across substrates with systematic neighbor analysis; 2-aminopurine fluorescence and single-turnover kinetics for base-flipping

    PMID:11015203 PMID:11041852

    Open questions at the time
    • Atomic basis of neighbor preference not resolved until later crystallography
    • Did not address how dsRBDs contribute to selectivity
  3. 2001 High

    Localized the dominant determinant of substrate specificity to the deaminase domain and identified the opposing-base mismatch as a recognition feature.

    Evidence In vitro editing with ADAR1/ADAR2 deaminase-domain chimeras and 20 mutated substrates

    PMID:11421361

    Open questions at the time
    • Structural explanation pending
    • Relative contribution of dsRBDs vs deaminase domain quantitatively unresolved
  4. 2003 High

    Uncovered two cis-acting autoregulatory layers—autoediting-driven alternative splicing and intron/exon duplex formation—that tune ADAR2 expression and target choice.

    Evidence deltaECS knock-in mouse abolishing autoediting plus Western and substrate-editing readouts; conservation and mutational analysis of the intron4/exon5 duplex

    PMID:14660658 PMID:16382140

    Open questions at the time
    • Quantitative contribution of autoediting to total ADAR2 output in vivo unclear
    • Interplay between autoediting and other regulators not integrated
  5. 2003 High

    Identified nucleolar sequestration via rRNA binding as a spatial mechanism limiting access to nucleoplasmic pre-mRNA substrates.

    Evidence Fluorescence microscopy, FRAP, rRNA-synthesis inhibition, dsRBD mutagenesis with editing readout

    PMID:14612560

    Open questions at the time
    • Signals controlling nucleolar/nucleoplasmic partitioning in vivo not defined
    • Whether partitioning is dynamically regulated by physiological cues unaddressed
  6. 2005 High

    Solved how the deaminase domain works at atomic resolution, revealing the catalytic zinc and the unexpected requirement for a buried IP6 cofactor.

    Evidence 1.7 Å crystal structure plus IP6 depletion/addition activity assays

    PMID:16141067

    Open questions at the time
    • No RNA-bound structure in this study
    • How IP6 occupancy is regulated in cells unknown
  7. 2005 High

    Showed RNA editing occurs in the nucleolus and that a brain-specific C/D snoRNA (MBII-52) site-specifically represses editing via competing 2'-O-methylation.

    Evidence Subcellular-targeted minigene editing substrates and snoRNP characterization

    PMID:15939761

    Open questions at the time
    • Generality of snoRNA-mediated repression beyond 5-HT2C unknown
    • Quantitative impact in native neuronal context not established
  8. 2006 High

    Defined the structural basis of dsRBM recognition of substrate stem-loops and the requirement for ternary complex/dimer formation in efficient editing.

    Evidence NMR of the two rat dsRBMs on the R/G substrate; EMSA, RNA-dependent crosslinking, kinetics; BRET dimerization in living cells with DRBM mutagenesis

    PMID:12163487 PMID:16472753 PMID:16682559

    Open questions at the time
    • Stoichiometry and architecture of the active dimer on RNA not fully resolved
    • Differential roles of DRBM1 vs DRBM2 in dimerization vs catalysis only partly explained
  9. 2010 High

    Extended Q/R-editing dependence to motor neuron survival, defining an editing-loss mechanism for ALS-like degeneration.

    Evidence Conditional ADAR2 knockout in motor neurons with pre-edited GluA2 knock-in rescue

    PMID:20826656

    Open questions at the time
    • Basis of oculomotor neuron resistance despite reduced editing unexplained
    • Link to sporadic human ALS not established here
  10. 2010 High

    Identified post-translational control of ADAR2 abundance and localization through Pin1-dependent stabilization and WWP2-mediated ubiquitin degradation.

    Evidence Reciprocal Co-IP, ubiquitination assays, Pin1-/- MEF localization and editing analysis

    PMID:21847096

    Open questions at the time
    • Phosphosites priming Pin1 binding not fully mapped
    • In vivo significance for neuronal editing not directly tested in this study
  11. 2012 Medium

    Identified trans-acting protein repressors of editing, showing site-specific control by RNA-interacting proteins coupled to neuronal activity.

    Evidence Co-IP plus overexpression/knockdown editing assays for RPS14, SFRS9, DDX15 with neuronal stimulation

    PMID:23275536

    Open questions at the time
    • Mechanism by which each repressor blocks editing differs and is incompletely defined
    • Effect sizes (~15%) leave open physiological magnitude
  12. 2016 High

    Placed ADAR2 in the circadian clock as a CLOCK-BMAL1 transcriptional target whose rhythmic editing shapes mRNA oscillations and behavior.

    Evidence CLOCK ChIP-seq, RNA-seq in knockout vs wild-type mice, circadian behavioral phenotyping

    PMID:27893733

    Open questions at the time
    • Which specific edited transcripts drive the locomotor phenotype not pinpointed
    • Mechanism connecting editing to CRY2 accumulation unresolved
  13. 2016 Medium

    Established ADAR2 editing as an editing-dependent tumor suppressor in glioma, identifying CDC14B and miRNA substrates that restrain proliferation and invasion.

    Evidence ADAR2 and catalytic-mutant rescue in astrocytoma lines, in vivo tumor assays, editing quantification, deep sequencing of miRNAs

    PMID:18178553 PMID:22525274 PMID:25582055 PMID:29267965

    Open questions at the time
    • Relative contribution of individual targets to tumor suppression unclear
    • ADAR1-ADAR2 heterodimer interference quantitatively undefined
  14. 2017 Medium

    Identified an editing-independent RNA-stabilizing function whereby ADAR2 binding shields transcripts from HuR/PARN-mediated decay.

    Evidence RNA half-life assays, RIP, editing-dead mutant rescue, PARN/HuR knockdown for Ctn RNA

    PMID:28053121

    Open questions at the time
    • Breadth of editing-independent targets not fully cataloged
    • Structural basis of protective binding unknown
  15. 2018 Medium

    Defined kinase inputs linking metabolic and signaling state to ADAR2 activity and abundance.

    Evidence PKCζ phosphorylation/editing assays with xenograft (CRC); JNK1/c-Jun promoter analysis and JNK1/2 knockout islets

    PMID:20501795 PMID:23139803 PMID:29694894

    Open questions at the time
    • PKCζ phosphosites on ADAR2 not mapped
    • Mechanistic link between editing and insulin-exocytosis effectors (Munc18-1, synaptotagmin-7) indirect
  16. 2018 Medium

    Showed SRSF9 represses brain-specific editing by disrupting ADAR2 dimerization, mechanistically connecting a splicing factor to editing control.

    Evidence Nuclear Co-IP, RRM2 domain mapping, dimerization assay, transcriptome-wide CLIP and RNA-seq

    PMID:29992293

    Open questions at the time
    • Whether other dimer-disrupting factors act similarly unknown
    • Physiological control of SRSF9 levels in neurons not defined
  17. 2020 High

    Connected ADARB1 to human disease, establishing biallelic loss-of-function as causative of microcephaly, intellectual disability, and epileptic encephalopathy.

    Evidence Recombinant mutant editing assays in HEK293T, ex vivo fibroblast editing, splicing analysis across multiple families

    PMID:32220291

    Open questions at the time
    • Which dysregulated substrates drive the neurological phenotype not defined
    • Genotype-phenotype correlation across variants incomplete
  18. 2023 High

    Resolved how RNA-binding-domain architecture encodes ADAR2's distinct editing footprint and structural offset, and extended its physiology to vascular immunity.

    Evidence Large-scale synthetic-substrate probing with domain swaps; endothelial-specific ADAR2 knockout with leukocyte rolling/adhesion and gp130/miRNA-processing assays

    PMID:37100060 PMID:38081817

    Open questions at the time
    • Structural mechanism of the -26 nt offset not solved
    • Identity of all edited targets suppressing Drosha processing incomplete
  19. 2022 High

    Comprehensively mapped sequence-function relationships in the deaminase domain, yielding engineered hyperactive and high-specificity editing tools.

    Evidence Deep mutational scanning across 261 residues with in-cell editing and split-domain engineering

    PMID:35044296

    Open questions at the time
    • Effects of variants in dsRBD/regulatory regions not scanned
    • In vivo behavior of engineered variants untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many regulatory inputs (nucleolar sequestration, autoediting, Pin1/WWP2, kinases, protein repressors) are integrated to set tissue- and condition-specific editing outputs remains unresolved.
  • No unified quantitative model coupling localization, abundance, and dimerization to per-site editing efficiency
  • Substrate-by-substrate physiological consequences of editing changes largely uncharacterized
  • Structural mechanism of dimer-on-RNA catalysis not solved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0003723 RNA binding 4 GO:0016787 hydrolase activity 2
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3 GO:0005730 nucleolus 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-9909396 Circadian clock 1
Partners
ADAR1DDX15KPNA3PIN1PRKCZRPS14SRSF9WWP2

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ADAR2 (ADARB1) is the primary enzyme responsible for A-to-I editing at the Q/R site of GluR-B (AMPA receptor subunit GluA2) pre-mRNA in vivo. ADAR2-null mice show substantially reduced editing at 25 positions across diverse transcripts; the lethal seizure phenotype is entirely rescued by engineering the edited codon directly into both GluA2 alleles, establishing GluA2 Q/R site editing as the physiologically critical substrate. Targeted knockout mouse (ADAR2-/-) combined with knock-in rescue using pre-edited GluA2 alleles; genetic epistasis Nature High 10894545
2005 The crystal structure of the human ADAR2 catalytic domain at 1.7 Å resolution reveals a zinc ion in the active site and an unexpectedly buried inositol hexakisphosphate (IP6) molecule that contributes to the protein fold and is required for deaminase activity. IP6 coordinates are conserved in related tRNA adenosine deaminases (ADATs), which also require IP6. X-ray crystallography (1.7 Å resolution) + in vitro deaminase activity assays with IP6 depletion/addition Science High 16141067
2016 Crystal structures of the human ADAR2 deaminase domain bound to RNA duplexes bearing a deamination-intermediate mimic reveal a base-flipping mechanism for substrate adenosine, the structural basis for dsRNA specificity and nearest-neighbor preferences, and an ADAR2-specific RNA-binding loop near the active site that rationalizes selectivity differences between ADAR family members. X-ray crystallography (four structures) + structure-guided mutagenesis + RNA-modification experiments Nature structural & molecular biology High 27065196
2010 NMR solution structure of the ADAR2 double-stranded RNA-binding motifs (dsRBMs) bound to GluR-2 R/G editing site pre-mRNA stem-loop reveals that dsRBMs achieve sequence-specific recognition of dsRNA through direct readout of the RNA primary sequence via the minor groove, a mechanism critical for both editing and binding affinity at this site. NMR solution structure + binding affinity measurements + mutagenesis of protein and RNA Cell High 20946981
2003 ADAR2 edits its own pre-mRNA (autoediting) to create a proximal 3' splice site containing a non-canonical AI dinucleotide; alternative splicing to this site introduces a frameshift causing premature translation termination, reducing ADAR2 protein expression. Mice lacking the editing-site complementary sequence (ECS) show abolished ADAR2 autoediting, increased ADAR2 protein, and correspondingly increased editing of ADAR2 substrates, demonstrating autoediting as a negative feedback regulatory mechanism. Knock-in mouse (deltaECS) abolishing autoediting site + Western blot for ADAR2 protein + substrate editing quantification Molecular and cellular biology High 14660658 16382140
2003 ADAR2 concentrates in the nucleolus via its dsRNA-binding domains (interaction with ribosomal RNA); inhibition of rRNA synthesis or dsRBD mutation causes translocation to the nucleoplasm. FRAP shows rapid shuttling between compartments. Forced translocation to the nucleoplasm increases editing of endogenous ADAR2 substrates, indicating that nucleolar sequestration regulates ADAR2 editing activity by limiting access to nucleoplasmic pre-mRNA substrates. Fluorescence microscopy + FRAP + rRNA synthesis inhibition + dsRBD mutagenesis + substrate editing quantification Proceedings of the National Academy of Sciences of the United States of America High 14612560
2005 ADAR2-mediated RNA editing occurs in the nucleolus. The brain-specific C/D small nucleolar RNA MBII-52 forms a bona fide snoRNP and specifically decreases ADAR2 editing efficiency at the C-site of 5-HT2C serotonin receptor pre-mRNA by targeting it for 2'-O-methylation, demonstrating C/D snoRNA-mediated regulation of site-specific RNA editing. Subcellular targeting of minigene editing substrates + snoRNP characterization + editing efficiency assays The Journal of cell biology High 15939761
2000 ADAR2 has a 5' neighbor preference (~U > C = G) and additionally a 3' neighbor preference (U = G > C = A) for deamination, with preferred trinucleotide sequences (UAU, AAG, UAG, AAU). ADAR1 and ADAR2 deaminate a given RNA with the same selectivity (fraction of adenosines edited at completion), indicating selectivity is dictated by RNA substrate features rather than enzyme identity. In vitro deamination assays comparing human ADAR1 and ADAR2 on multiple substrates with systematic neighbor analysis Biochemistry High 11041852
2001 The deaminase domain of ADAR2 plays a dominant role in determining substrate specificity. An A:C mismatch at the editing site enhances editing by both ADAR1 and ADAR2 compared to A:A, A:G mismatches or A:U base pairs, suggesting the opposing base influences substrate recognition and/or catalysis. In vitro editing assays with 20 mutated substrates derived from four editing sites + ADAR1/ADAR2 deaminase domain chimeras RNA High 11421361
1997 Four alternatively spliced isoforms of human DRADA2 (ADAR2/ADARB1) exhibit different RNA editing site selectivity: DRADA2a and -2b isoforms efficiently edit the GluR-B Q/R site (which DRADA1/ADAR1 barely edits) and the R/G site; truncated isoforms DRADA2c and -2d show only weak adenosine-to-inosine activity and no site-specific editing at three known GluR-B sites. In vitro editing assays with recombinant isoforms on GluR-B RNA substrates Molecular and cellular biology High 9111310
2011 Pin1, a phosphorylation-dependent prolyl-isomerase, interacts with ADAR2 and is required for its nuclear localization and protein stability. The E3 ubiquitin ligase WWP2 binds ADAR2 and catalyzes its ubiquitination and subsequent proteasomal degradation. Pin1-/- fibroblasts show ADAR2 mislocalization to the cytoplasm and reduced editing at GluR2 Q/R and R/G sites. Co-immunoprecipitation + ubiquitination assay + Pin1-/- MEF localization and editing analysis The EMBO journal High 21847096
2017 During neuronal development, the nuclear importer importin-α4 (Kpna3) interacts with ADAR2 and promotes its nuclear accumulation; the nuclear isomerase Pin1 also increases ADAR2 protein stability as neurons mature. These interactions explain the developmental increase in nuclear A-to-I editing of neuronal transcripts from low embryonic to high postnatal levels. Co-immunoprecipitation + fractionation (nuclear/cytoplasmic) + editing efficiency assays during neuronal maturation Journal of cell science Medium 28082424
2006 Dimerization of rat ADAR2 is mediated by its double-stranded RNA-binding domains (DRBMs). BRET demonstrates ADAR2 dimerization in living mammalian cells. Mutation of DRBM1 reduces dimerization affinity while mutation of DRBM2 does not, yet DRBM2 function is required for efficient Q/R site editing, indicating that DRBMs serve differential roles in dimerization versus catalytic editing. In vitro dimerization assays + BRET in living cells + DRBM mutagenesis + editing activity assays RNA High 16682559
2002 ADAR2 editing of the GluR-B R/G site requires formation of a ternary (dimeric) complex on the RNA: gel shift analysis shows two complexes formed with increasing protein concentration; ADAR monomers can be cross-linked to each other in an RNA-dependent fashion; kinetic data are consistent with a rate-determining step being formation of the ADAR2·RNA ternary complex for efficient editing. Gel shift (EMSA) + RNA-dependent cross-linking + kinetic analysis of editing reaction The Journal of biological chemistry High 12163487
2000 ADAR2 induces a 3.3-fold fluorescence enhancement and blue shift in emission when 2-aminopurine is placed at the R/G editing site, consistent with a base-flipping mechanism in which ADAR2 extrudes the reactive adenosine from the double helix prior to deamination. Five base pairs of duplex 5' to the editing site increase single-turnover deamination rate 17-39 fold. Fluorescence spectroscopy with 2-aminopurine substrate analog + single-turnover kinetics Biochemistry Medium 11015203
2004 ADAR2's two dsRNA-binding motifs (dsRBMs) bind selectively at defined positions on a duplex RNA mimicking the GluR-B Q/R editing site; this binding selectivity differs from that of PKR dsRBM1. Blocking predicted dsRBM recognition surfaces by N2-benzyl modification of guanosine impedes RNA editing, demonstrating that dsRBM binding-site selectivity contributes to editing-site selectivity. Directed hydroxyl radical cleavage + molecular modeling + N2-benzylguanosine RNA modification + in vitro editing assays Chemistry & biology Medium 15380184
2006 NMR structures of the two dsRBMs of rat ADAR2 reveal that dsRBM1 recognizes a conserved pentaloop in the GluR-B R/G site substrate RNA, while dsRBM2 recognizes two bulged bases adjacent to the editing site, demonstrating RNA structure-dependent (not purely sequence-nonspecific) recognition. In vitro mutagenesis of both protein and RNA confirmed the structural contacts. NMR structure determination + NMR chemical shift perturbation study + mutagenesis of protein and RNA Structure High 16472753
2005 NMR solution structure of the GluR-B R/G site RNA stem-loop reveals a novel pentaloop fold (GCU(A/C)A) conserved in mammals and birds, stabilized by hydrogen bonds and stacking. This novel fold is proposed as an important structural determinant for ADAR2 substrate recognition at the R/G site. NMR solution structure determination RNA Medium 15840813
2003 Both evolutionary conservation and mutational analysis identify an extended RNA duplex in ADAR2 pre-mRNA formed by base-pairing between intron 4 and exon 5 sequences ~1.3 kb apart, containing 16 editing sites. ADAR2 preferentially modifies its own transcript among a mixed substrate population, and mutation of poor substrates to match a defined nucleotide bias increases ADAR2-mediated deamination, suggesting both sequence and structural elements define ADAR2 target selectivity. Sequence conservation analysis + mutational analysis + in vitro and tissue culture editing assays The Journal of biological chemistry Medium 14660658
2012 Three RNA-interacting proteins—RPS14, SFRS9, and DDX15—act as site-specific repressors of ADAR2-mediated RNA editing. SFRS9 and RPS14 directly interact with ADAR2 (shown by co-immunoprecipitation); overexpression or depletion alters editing at specific substrates (CFLAR, cyFIP2) by up to 15% each, and SFRS9/DDX15 levels respond to neuronal stimulation inversely correlating with editing levels. Co-immunoprecipitation + overexpression/knockdown with substrate-specific editing assays + neuronal stimulation experiments Nucleic acids research Medium 23275536
2018 PKCζ phosphorylates ADAR2 in colorectal cancer cells; this phosphorylation by PKCζ regulates ADAR2 editing activity, which in turn maintains steady-state levels of miR-200 family members, controlling their secretion in extracellular vesicles. Loss of the PKCζ/ADAR2 axis results in epithelial-to-mesenchymal transition and liver metastasis. Co-immunoprecipitation + phosphorylation assays + editing activity assays + in vivo xenograft model Cell reports Medium 29694894
2015 ADAR2 edits miR-222/221 and miR-21 precursors in vitro and in vivo, and its rescue in glioblastoma cells decreases expression of these onco-miRNAs. ADAR2 broadly reduces expression of ~90 miRNAs in glioblastoma cells, with the major effect being suppression of onco-miRNAs, rebalancing the miRNome toward the normal brain pattern. Deep sequencing + array analysis + ADAR2 rescue in cell lines and tissues + cell proliferation/migration assays Genome biology Medium 25582055
2018 ADAR2-mediated editing of miR-589-3p seed sequence retargets this miRNA from tumor-suppressor PCDH9 to ADAM12 (a metalloproteinase promoting invasion). The edited miR-589-3p inhibits glioblastoma cell proliferation, migration and invasion, whereas the unedited form promotes them. Deep sequencing + target validation assays + ADAR2 knockdown/rescue + cell functional assays (proliferation, migration, invasion) Nucleic acids research Medium 29267965
2016 ADAR2 editing of CDC14B pre-mRNA in astrocytomas increases CDC14B expression, which in turn reduces Skp2 protein levels, causing accumulation of p21 and p27 and inhibiting cell cycle progression. CDC14B is identified as a novel ADAR2 target gene linking ADAR2 editing activity to tumor suppression in glioblastoma. ADAR2 rescue in astrocytoma cell lines (including catalytically inactive mutant) + in vivo tumor growth assay + editing quantification of CDC14B + Western blot for Skp2/p21/p27 Oncogene Medium 22525274
2016 ADAR2 editing activity inhibits astrocytoma/glioblastoma cell migration and proliferation in a manner dependent on its catalytic (editing) activity, as reintroduction of wild-type but not inactive ADAR2 into astrocytoma cell lines reverts malignant behavior. Endogenous ADAR1 can form heterodimers with ADAR2 in astrocytes and interferes with ADAR2-specific editing. ADAR2 and catalytic-mutant ADAR2 reintroduction in astrocytoma cell lines + proliferation/migration/cell cycle assays + Co-immunoprecipitation for ADAR1-ADAR2 heterodimer The Journal of biological chemistry Medium 18178553
2016 ADARB1/ADAR2 expression is under circadian CLOCK-ARNTL (BMAL1) transcriptional control; ADAR2-mediated A-to-I editing of diverse transcripts is rhythmic. In Adarb1-knockout mice, circadian mRNA oscillation is broadly attenuated and locomotor period is shortened, associated with abnormal accumulation of CRY2. CLOCK-ChIP-seq + RNA-seq in knockout and wild-type mice + behavioral circadian phenotyping Nature genetics High 27893733
2017 ADAR2 stabilizes the nuclear-retained Ctn RNA by an editing-independent mechanism: ADAR2 binding to the 3'UTR of Ctn RNA blocks access of the RNA-destabilizing proteins HuR and PARN, thereby preventing Ctn RNA degradation. This stabilization mechanism extends to other ADAR2-associated transcripts identified by transcriptomic analysis. RNA half-life assays + RIP (RNA immunoprecipitation) + ADAR2 knockdown/rescue including editing-dead mutant + PARN/HuR knockdown Nucleic acids research Medium 28053121
2010 ADAR2 deficiency in motor neurons (conditional knockout mice) causes slow progressive motor neuron death and ALS-like phenotype exclusively through expression of Q/R site-unedited GluA2, as demonstrated by complete rescue when ADAR2-null neurons carry pre-edited GluA2 alleles. Oculomotor neurons are resistant despite reduced Q/R editing. Conditional ADAR2 knockout in motor neurons (Cre/loxP) + rescue with pre-edited GluA2 knock-in allele The Journal of neuroscience High 20826656
2006 ADAR2 is a nuclear enzyme essential for GluR2 Q/R site editing; reduction in ADAR2 expression in forebrain ischemia disrupts this editing in vulnerable neurons. Exogenous ADAR2b expression or CREB-induced endogenous ADAR2 upregulation rescues editing and protects hippocampal neurons from ischemic death; ADAR2 siRNA knockdown inhibits editing and causes neurodegeneration of normally ischemia-insensitive neurons. Direct introduction of edited GluR2(R607) rescues ADAR2-knockdown-induced degeneration. In vivo rat ischemia model + viral ADAR2 gene delivery + siRNA knockdown + edited GluR2 gene delivery + editing quantification Neuron High 16504947
2010 ADAR2 deficiency in pancreatic β-cells impairs glucose-stimulated insulin secretion and Ca2+-evoked exocytosis (reduced membrane capacitance, fewer membrane-docked granules). The defect requires catalytically active ADAR2, as editing-dead mutant cannot rescue. ADAR2 deficiency decreases expression of Munc18-1 and synaptotagmin-7. ADAR2 knockdown + rescue with wild-type vs. editing-dead ADAR2 in INS-1 cells and primary islets + capacitance measurements + insulin/secretion assays FASEB journal Medium 20501795
2012 JNK1 (c-Jun amino-terminal kinase-1) mediates glucose-responsive upregulation of ADAR2 expression in pancreatic β-cells. JNK1 inhibition or knockdown suppresses glucose-augmented ADAR2 expression. Adar2 mRNA is selectively reduced in islets of JNK1-null but not JNK2-null mice. Promoter analysis identifies a glucose-responsive region and c-Jun as a transcriptional driver of Adar2. Pharmacological JNK inhibition + siRNA knockdown + JNK1/JNK2 knockout mice + Adar2 promoter analysis + ADAR2 autoediting assay PloS one Medium 23139803
2015 The isolated human ADAR2 deaminase domain protects approximately 23 nucleotides on the edited strand around the editing site in an asymmetric fashion (~18 nt on 5' side, ~5 nt on 3' side), as shown by ribonuclease V1 footprinting. The domain requires duplex RNA and is sensitive to 2'-deoxy substitution opposite the editing site. EMSA + ribonuclease V1 footprinting with 8-azanebularine (reaction-intermediate mimic) in RNA Nucleic acids research Medium 25564529
2018 SRSF9 (splicing factor) selectively represses ADAR2-mediated editing at brain-specific sites by biochemically interacting with ADAR2 via its RRM2 domain in the nucleus in an RNA-substrate-dependent manner. This interaction disrupts ADAR2 dimer formation and controls 1328 editing sites predominantly enriched for brain-specific targets. Co-immunoprecipitation (nuclear) + domain mapping (RRM2) + ADAR2 dimerization assay + transcriptome-wide CLIP and RNA-seq Nucleic acids research Medium 29992293
2023 ADAR2 and ADAR1 induce symmetric, strand-specific editing with distinct structural offsets: ADAR2 shows a -26 nt offset with respect to structural disruptions in dsRNA substrates, while ADAR1 shows -35 nt. This difference in offset is encoded by the differential RNA-binding domain (RBD) architecture of the two enzymes, as shown by domain-swap mutants and ADAR homologs. Systematic probing of thousands of synthetic sequences in cell lines expressing exclusively ADAR1 or ADAR2 + domain-swap mutants + ADAR homolog analysis Nature communications High 38081817
2022 Deep mutational scanning of the ADAR2 deaminase domain across 261 residues directly maps the impact of every amino acid substitution on RNA editing activity, revealing a novel hyperactive variant with improved activity at 5'-GAN-3' motifs. A split-ADAR2 deaminase (split at the deaminase domain) achieves >100-fold more specific RNA editing than full-length deaminase overexpression. Deep mutational scanning + in-cell RNA editing assay + split-domain engineering eLife High 35044296
2023 ADAR2 promotes immune cell trafficking in vascular endothelium by editing targets that suppress Drosha-dependent primary microRNA processing, thereby protecting expression of the IL-6 receptor subunit gp130 (IL6ST) and enabling IL-6 trans-signaling. Endothelial-specific ADAR2 knockout reduces myeloid cell rolling, adhesion, and immune infiltration in ischemic tissue. Endothelial-specific ADAR2 conditional knockout + leukocyte rolling/adhesion assays + gp130 expression quantification + miRNA processing assays Immunity High 37100060
2020 Biallelic loss-of-function variants in ADARB1 (encoding ADAR2) cause microcephaly, intellectual disability, and epileptic encephalopathy in humans. In vitro assays with recombinant proteins in HEK293T cells demonstrate that the identified missense variants reduce ADAR2 editing activity on a known substrate; one variant alters splicing of ADARB1 transcripts. In vitro RNA editing assays with recombinant mutant ADAR2 proteins + ex vivo fibroblast editing assays + splicing analysis American journal of human genetics High 32220291

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 825 10894545
2005 Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science (New York, N.Y.) 356 16141067
1997 The yeast Red1 protein localizes to the cores of meiotic chromosomes. The Journal of cell biology 270 9060462
2000 Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities. Biochemistry 235 11041852
2001 Substrate recognition by ADAR1 and ADAR2. RNA (New York, N.Y.) 208 11421361
2016 Structures of human ADAR2 bound to dsRNA reveal base-flipping mechanism and basis for site selectivity. Nature structural & molecular biology 203 27065196
2010 The solution structure of the ADAR2 dsRBM-RNA complex reveals a sequence-specific readout of the minor groove. Cell 198 20946981
2006 ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 185 16504947
2005 ADAR2-mediated editing of RNA substrates in the nucleolus is inhibited by C/D small nucleolar RNAs. The Journal of cell biology 181 15939761
2011 Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons. Neurobiology of disease 166 22226999
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2008 Down-regulation of RNA editing in pediatric astrocytomas: ADAR2 editing activity inhibits cell migration and proliferation. The Journal of biological chemistry 165 18178553
2003 Modulation of RNA editing by functional nucleolar sequestration of ADAR2. Proceedings of the National Academy of Sciences of the United States of America 161 14612560
2010 Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. The Journal of neuroscience : the official journal of the Society for Neuroscience 142 20826656
2015 Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma. Genome biology 128 25582055
2012 ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. Oncogene 127 22525274
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2003 Mek1 kinase activity functions downstream of RED1 in the regulation of meiotic double strand break repair in budding yeast. Molecular biology of the cell 116 14595109
2011 Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. The EMBO journal 113 21847096
2018 ADAR2/miR-589-3p axis controls glioblastoma cell migration/invasion. Nucleic acids research 112 29267965
2017 Harnessing human ADAR2 for RNA repair - Recoding a PINK1 mutation rescues mitophagy. Nucleic acids research 111 27907896
2006 Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. Structure (London, England : 1993) 106 16472753
2010 TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. Acta neuropathologica 104 20372915
2006 Altered RNA editing in mice lacking ADAR2 autoregulation. Molecular and cellular biology 94 16382140
2011 Requirement of the RNA-editing enzyme ADAR2 for normal physiology in mice. The Journal of biological chemistry 91 21467037
2003 Structure and sequence determinants required for the RNA editing of ADAR2 substrates. The Journal of biological chemistry 88 14660658
2011 Red1 promotes the elimination of meiosis-specific mRNAs in vegetatively growing fission yeast. The EMBO journal 87 21317872
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2009 ADAR1 and ADAR2 expression and editing activity during forebrain development. Developmental neuroscience 79 19325227
2002 Increased RNA editing and inhibition of hepatitis delta virus replication by high-level expression of ADAR1 and ADAR2. Journal of virology 76 11907222
2021 ADAR2 increases in exercised heart and protects against myocardial infarction and doxorubicin-induced cardiotoxicity. Molecular therapy : the journal of the American Society of Gene Therapy 73 34274534
2016 ADAR2 functions as a tumor suppressor via editing IGFBP7 in esophageal squamous cell carcinoma. International journal of oncology 69 28035363
2009 Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets. Molecular cancer therapeutics 68 19139135
2003 ADAR2 A-->I editing: site selectivity and editing efficiency are separate events. Nucleic acids research 68 12907730
2017 Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development. Journal of cell science 66 28082424
2016 ADARB1 catalyzes circadian A-to-I editing and regulates RNA rhythm. Nature genetics 66 27893733
2012 RNA-interacting proteins act as site-specific repressors of ADAR2-mediated RNA editing and fluctuate upon neuronal stimulation. Nucleic acids research 66 23275536
2007 Hyperphagia-mediated obesity in transgenic mice misexpressing the RNA-editing enzyme ADAR2. The Journal of biological chemistry 65 17567573
2003 Low editing efficiency of GluR2 mRNA is associated with a low relative abundance of ADAR2 mRNA in white matter of normal human brain. The European journal of neuroscience 65 12859334
2004 The binding selectivity of ADAR2's dsRBMs contributes to RNA-editing selectivity. Chemistry & biology 64 15380184
2000 In vitro analysis of the binding of ADAR2 to the pre-mRNA encoding the GluR-B R/G site. RNA (New York, N.Y.) 64 10836790
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2018 The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer. Cell reports 60 29694894
2013 Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons. EMBO molecular medicine 58 24115583
2011 Functional conservation in human and Drosophila of Metazoan ADAR2 involved in RNA editing: loss of ADAR1 in insects. Nucleic acids research 58 21622951
1997 Cloning of a human RNA editing deaminase (ADARB1) of glutamate receptors that maps to chromosome 21q22.3. Genomics 58 9143496
2006 Dimerization of ADAR2 is mediated by the double-stranded RNA binding domain. RNA (New York, N.Y.) 56 16682559
2001 Hepatitis delta virus minimal substrates competent for editing by ADAR1 and ADAR2. Journal of virology 56 11507200
2019 ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD. Acta neuropathologica 55 30945056
2006 RNA editing by ADAR2 is metabolically regulated in pancreatic islets and beta-cells. The Journal of biological chemistry 55 16956888
2000 Analysis of the RNA-editing reaction of ADAR2 with structural and fluorescent analogues of the GluR-B R/G editing site. Biochemistry 55 11015203
1993 A conditional allele of the Saccharomyces cerevisiae HOP1 gene is suppressed by overexpression of two other meiosis-specific genes: RED1 and REC104. Genetics 55 8462842
2010 Synaptonemal complex formation and meiotic checkpoint signaling are linked to the lateral element protein Red1. Proceedings of the National Academy of Sciences of the United States of America 54 20534433
2009 Yeast axial-element protein, Red1, binds SUMO chains to promote meiotic interhomologue recombination and chromosome synapsis. The EMBO journal 54 19959993
2002 Inhibition of hepatitis delta virus RNA editing by short inhibitory RNA-mediated knockdown of ADAR1 but not ADAR2 expression. Journal of virology 54 12414985
2014 A role of ADAR2 and RNA editing of glutamate receptors in mood disorders and schizophrenia. Molecular brain 49 24443933
2022 Targeting the androgen receptor to enhance NK cell killing efficacy in bladder cancer by modulating ADAR2/circ_0001005/PD-L1 signaling. Cancer gene therapy 47 35915245
1999 Synthetic substrate analogs for the RNA-editing adenosine deaminase ADAR-2. Nucleic acids research 47 10390533
2017 ADAR2 regulates RNA stability by modifying access of decay-promoting RNA-binding proteins. Nucleic acids research 44 28053121
2014 ADAR2 induces reproducible changes in sequence and abundance of mature microRNAs in the mouse brain. Nucleic acids research 42 25260591
2009 Novel exon of mammalian ADAR2 extends open reading frame. PloS one 42 19156214
2001 Cryoreduction of methyl-coenzyme M reductase: EPR characterization of forms, MCR(ox1) and MCR (red1). Journal of the American Chemical Society 42 11414817
2015 Recognition of duplex RNA by the deaminase domain of the RNA editing enzyme ADAR2. Nucleic acids research 41 25564529
2015 Nuclear factor 90 uses an ADAR2-like binding mode to recognize specific bases in dsRNA. Nucleic acids research 41 26712564
2004 The photomorphogenesis-related mutant red1 is defective in CYP83B1, a red light-induced gene encoding a cytochrome P450 required for normal auxin homeostasis. Planta 41 14963708
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2020 Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures. American journal of human genetics 40 32220291
2014 ADAR2-dependent GluA2 editing regulates cocaine seeking. Molecular psychiatry 40 25349168
2013 RNA-Seq analysis identifies a novel set of editing substrates for human ADAR2 present in Saccharomyces cerevisiae. Biochemistry 40 24124932
2002 Phylogenetic comparison of the pre-mRNA adenosine deaminase ADAR2 genes and transcripts: conservation and diversity in editing site sequence and alternative splicing patterns. Gene 39 12459255
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2011 When Does ALS Start? ADAR2-GluA2 Hypothesis for the Etiology of Sporadic ALS. Frontiers in molecular neuroscience 38 22102833
2007 Altered editing in RNA editing adenosine deaminase ADAR2 gene transcripts of systemic lupus erythematosus T lymphocytes. Immunology 37 17376196
2002 Adenosine to inosine editing by ADAR2 requires formation of a ternary complex on the GluR-B R/G site. The Journal of biological chemistry 37 12163487
2015 Joint effect of ADARB1 gene, HTR2C gene and stressful life events on suicide attempt risk in patients with major psychiatric disorders. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 35 25732952
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2001 The nickel enzyme methyl-coenzyme M reductase from methanogenic archaea: in vitro interconversions among the EPR detectable MCR-red1 and MCR-red2 states. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 35 11862546
2011 ADAR2 editing enzyme is a novel human immunodeficiency virus-1 proviral factor. The Journal of general virology 33 21289159
2023 Dissecting the basis for differential substrate specificity of ADAR1 and ADAR2. Nature communications 32 38081817
2013 ADAR2-mediated editing of miR-214 and miR-122 precursor and antisense RNA transcripts in liver cancers. PloS one 30 24386085
2024 Nanocarriers Targeting Circular RNA ADARB1 Boost Radiosensitivity of Nasopharyngeal Carcinoma through Synergically Promoting Ferroptosis. ACS nano 28 39467079
2016 Probing RNA recognition by human ADAR2 using a high-throughput mutagenesis method. Nucleic acids research 28 27614075
2010 Selective inhibition of ADAR2-catalyzed editing of the serotonin 2c receptor pre-mRNA by a helix-threading peptide. Organic & biomolecular chemistry 28 20820662
2020 Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy. Journal of medical genetics 27 32719099
2018 SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates. Nucleic acids research 27 29992293
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2003 Biochemical analysis and scanning force microscopy reveal productive and nonproductive ADAR2 binding to RNA substrates. RNA (New York, N.Y.) 27 12810917
2020 Mutations in cardinal are responsible for the red-1 and peach eye color mutants of the red flour beetle Tribolium castaneum. Biochemical and biophysical research communications 26 32703438
2015 Decrease of mRNA Editing after Spinal Cord Injury is Caused by Down-regulation of ADAR2 that is Triggered by Inflammatory Response. Scientific reports 26 26223940
2018 Cell death cascade and molecular therapy in ADAR2-deficient motor neurons of ALS. Neuroscience research 25 29944911
2012 c-Jun amino-terminal kinase-1 mediates glucose-responsive upregulation of the RNA editing enzyme ADAR2 in pancreatic beta-cells. PloS one 25 23139803
2010 ADAR2-dependent RNA editing of GluR2 is involved in thiamine deficiency-induced alteration of calcium dynamics. Molecular neurodegeneration 25 21110885
2010 A novel tissue-specific alternatively spliced form of the A-to-I RNA editing enzyme ADAR2. RNA biology 24 20215858
2010 Deficiency in RNA editing enzyme ADAR2 impairs regulated exocytosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 20501795
2022 ADAR2 enzymes: efficient site-specific RNA editors with gene therapy aspirations. RNA (New York, N.Y.) 23 35863867
2021 The zinc-finger protein Red1 orchestrates MTREC submodules and binds the Mtl1 helicase arch domain. Nature communications 23 34103492
2023 The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation. Immunity 22 37100060
2017 RNA-editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA. FEBS letters 22 28833069
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