| 2015 |
A-to-I editing of endogenous dsRNA by ADAR1 is the essential function required to prevent activation of the cytosolic dsRNA sensor MDA5. Editing-deficient knock-in mice (E861A) died at ~E13.5 with activated interferon and dsRNA-sensing pathways; embryonic death was rescued by concurrent deletion of MDA5. Genome-wide analysis identified clustered hyperediting within long dsRNA stem loops in 3' UTRs of endogenous transcripts as primary ADAR1 substrates. |
Editing-deficient knock-in mouse (E861A), genetic rescue by MDA5 deletion, genome-wide substrate mapping |
Science |
High |
26275108
|
| 2018 |
ADAR1 prevents translational shutdown by inhibiting hyperactivation of PKR, a dsRNA sensor. In ADAR1 knockout human cells, endogenous Alu elements in pol II-transcribed mRNAs were the primary editing substrates. Both dsRNA binding and catalytic activities of ADAR1 were required to fully prevent endogenous RNA from activating PKR. ADAR1 knockout neuronal progenitor cells exhibited MDA5-dependent spontaneous interferon production, PKR activation, and cell death. |
ADAR1 knockout human cells, mechanistic dissection with catalytic and dsRNA-binding mutants, cell-type specific phenotyping |
Cell |
High |
29395325
|
| 2014 |
Adar1 embryonic lethality is rescued to live birth in Adar1;Mavs double mutants, demonstrating that the antiviral interferon induction response to cytoplasmic dsRNA drives the lethal phenotype. Restoring editing-active cytoplasmic ADAR1 dramatically reduced aberrant immune responses in Adar1 mutant MEFs. dsRNA oligonucleotides containing inosine-uracil base pairs reduced the aberrant innate immune response, consistent with inosine in cellular RNA inhibiting RLR interactions. |
Genetic rescue (double mutant mice), MEF transfection with inosine-containing dsRNA, reintroduction of editing-active ADAR1 |
Cell reports |
High |
25456137
|
| 2022 |
ADAR1 inhibits spontaneous activation of ZBP1 by preventing accumulation of endogenous Z-form dsRNAs (Z-RNAs). The Zα domain of ADAR1 promotes A-to-I editing of endogenous Alu elements to prevent dsRNA formation through pairing of inverted Alu repeats, which can otherwise activate ZBP1. ZBP1 activation in ADAR1-deficient cells elicits caspase-8-dependent apoptosis and MLKL-mediated necroptosis. ZBP1 contributes to embryonic lethality of Adar-knockout mice. |
Adar knockout mice, Adar;Mavs double mutants, Zα domain mutation, cell death pathway analysis |
Nature |
High |
35859175 35859176 35859177
|
| 2022 |
The ZBD (Zα domain) point mutation of ADAR1 drives pathology through ZBP1 activation. Ablation of ZBP1 fully rescued overt pathology caused by ADAR1 Zα domain alteration. Loss of RIPK3 partially phenocopied ZBP1 ablation, while combined deletion of caspase-8 and RIPK3, or caspase-8 and MLKL, exacerbated pathogenic effects, indicating ZBP1-dependent signaling underlies the autoinflammatory pathology. |
Genetic epistasis in mice: Adar1 ZBD mutant crossed with ZBP1 KO, RIPK3 KO, caspase-8/RIPK3 double KO, caspase-8/MLKL double KO |
Nature |
High |
35859177
|
| 2022 |
ADAR1 Zα domain prevents endogenous Z-RNA-dependent activation of ZBP1 that drives type I IFN responses. ZBP1 deficiency or mutation of its Zα domains reduced IFN-stimulated gene expression and prevented early postnatal lethality in Adar1mZα/- mice. ZBP1 promoted IFN activation independently of RIPK1, RIPK3, MLKL-mediated necroptosis and caspase-8-dependent apoptosis, suggesting a novel signaling mechanism. Adar1mZα/- mice showed upregulation and impaired editing of endogenous retroelement-derived complementary RNA reads as a likely Z-RNA source. |
Adar1mZα/- mouse model, ZBP1 deficiency rescue, Zα domain mutation of ZBP1, RNA sequencing |
Nature |
High |
35859176
|
| 2022 |
ADAR1 prevents accumulation of endogenous Z-RNA elements enriched in 3' UTRs of interferon-stimulated mRNAs. Depletion or mutation of ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, culminating in RIPK3-mediated necroptosis. ADAR1 interaction with ZBP1 Zα2 domain limits ZBP1 and RIPK3 interactions, suppressing PANoptosis. |
ADAR1 depletion, Z-RNA detection, ZBP1 activation assay, RIPK3 functional analysis, co-immunoprecipitation of ADAR1 with ZBP1 |
Nature |
High |
34686350 35614224
|
| 2021 |
ADAR1 suppresses ZBP1-mediated PANoptosis by directly interacting with the Zα2 domain of ZBP1, limiting ZBP1-RIPK3 interactions. Combining interferons and nuclear export inhibitors activates ZBP1-dependent PANoptosis. Adar1fl/fl LysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis. |
Co-immunoprecipitation, genetic mouse models (Adar1 conditional KO, ZBP1 Zα2 domain deletion), tumor models |
Cell reports |
High |
34686350
|
| 2024 |
ADAR1 dsRBD3 directly interacts with the PKR kinase domain on dsRNA to inhibit PKR activation. AlphaFold modeling predicted an inhibitory ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA. Wild-type or editing-inactive human ADAR1 expressed in A549 cells inhibited activation of endogenous PKR. ADAR1 dsRNA binding is required but not sufficient for PKR inhibition; mutating the ADAR1 dsRBD3-PKR contact prevented co-immunoprecipitation, PKR inhibition, and co-localization. Adar Mavs Eifak2 (Pkr) triple mutant mice rescued all defects and showed long-term survival. |
Co-immunoprecipitation, editing-inactive ADAR1 mutant, dsRBD3-PKR contact mutant, AlphaFold structural modeling, triple-mutant mouse model |
Cell reports |
High |
39146181
|
| 2025 |
PACT cooperates with ADAR1 to suppress PKR activation by self-dsRNAs. Simultaneous deletion of PACT and ADAR1 results in synthetic lethality, fully rescued in PKR-deficient cells. PACT-deficient cells hyperactivate PKR in response to RNA viruses. |
FACS-based genome-wide CRISPR-Cas9 knockout screen (CRISPR-Translate), double KO synthetic lethality, PKR KO rescue |
Nature communications |
High |
40185749
|
| 2021 |
ADAR1 p150 and p110 have distinct editing preferences determined primarily by their intracellular localization, not by the Zα domain. More than half of A-to-I edit sites are selectively edited by p150, while the other half are edited by either p150 or p110. p110 is co-expressed with p150 from the canonical p150-encoding mRNA due to leaky ribosome scanning downstream of the p150 start codon. |
ADAR1 KO cells reconstituted with modified isoform-selective constructs, RNA editing analysis, synonymous mutation to prevent leaky scanning |
PNAS |
High |
33723056
|
| 2023 |
Isoform-specific editing by ADAR1 is primarily directed by intracellular localization (cytoplasmic p150 vs. nuclear p110), with ZBDα only minimally contributing to p150-specific editing preferences. ADAR1p110 preferentially binds and edits intronic sequences while ADAR1p150 preferentially binds and edits 3' UTRs. |
Transfection of ADAR1 isoforms into ADAR-less mouse cells, localization mutants, Zα domain mutants, RIP-seq |
Nucleic acids research |
High |
37026479
|
| 2020 |
ADAR1 is downregulated by autophagic degradation during cellular senescence, driving senescence through p16INK4a upregulation in an RNA-editing-independent manner. Mechanistically, ADAR1 promotes SIRT1 expression by affecting its RNA stability through HuR. SIRT1 antagonizes translation of mRNA encoding p16INK4a. ADAR1 downregulation is sufficient to drive senescence both in vitro and in vivo. |
Autophagic degradation assay, ADAR1 KD/KO in vitro and in vivo, editing-inactive mutant, HuR interaction, SIRT1/p16INK4a pathway analysis |
Nature cell biology |
High |
35851616
|
| 2018 |
ADAR1 controls ITGB3 expression and melanoma cell invasiveness via editing-independent mechanisms: ADAR1 regulates miR-22 expression through FOXD1 transcription factor, and miR-22 directly regulates ITGB3 expression. ADAR1 also regulates ITGB3 at the transcriptional level via PAX6. Re-expression of either wild-type or catalytically inactive ADAR1 reversed the enhanced invasion caused by ADAR1 silencing. |
ADAR1 silencing/re-expression, catalytically inactive ADAR1 mutant, ITGB3 antibody blockade, miR-22/FOXD1/PAX6 pathway analysis |
Nature communications |
High |
29855470
|
| 2023 |
ADAR1 interacts with TOPBP1 and facilitates TOPBP1 loading on perturbed replication forks by enhancing TOPBP1 association with RAD9 of the 9-1-1 complex, thereby promoting ATR activation. When replication is inhibited, DNA-RNA hybrids (R-loops) compete with TOPBP1 for ADAR1 binding, causing ADAR1 translocation from damaged forks to R-loop regions where it recruits RNA helicases DHX9 and DDX21 to unwind R-loops. ADAR1's dsRNA-binding domains are required for this function. |
Co-immunoprecipitation, proximity ligation, ADAR1 dsRBD mutants, R-loop detection (S9.6 antibody), ATR activation assays, helicase interaction studies |
Nucleic acids research |
High |
37831098
|
| 2016 |
ADAR1 suppresses LINE-1 (L1) retrotransposition independently of its editing activity. ADAR1 was found in the basal L1 RNP complex. By dual-tag affinity purification during HIV-1 expression, 14 non-ribosomal ADAR1-interacting proteins were identified, many associated with LINE-1 ribonucleoparticles. |
Dual-tag affinity purification, mass spectrometry, cell-culture retrotransposition assays (editing-inactive ADAR1 mutant) |
Nucleic acids research |
Medium |
27658966
|
| 2023 |
ADAR1 interacts with Drosha to promote its degradation, attenuating Drosha-DGCR8 interaction and consequently inhibiting pri- to pre-microRNA processing of microRNAs targeting IKKβ. This results in increased IKKβ expression and enhanced NF-κB signaling in macrophages, promoting vascular inflammation. This function is editing-independent. |
Co-immunoprecipitation (ADAR1-Drosha interaction), macrophage-specific ADAR1 KO, aortic transplantation, human AAA specimens, humanized AAA model |
Circulation research |
High |
36688311
|
| 2013 |
ADAR1 forms a complex with Dicer via direct protein-protein interaction. ADAR1 in the Dicer complex promotes pre-miRNA cleavage by Dicer and facilitates miRNA loading onto RISC, stimulating miRNA processing and RNAi. ADAR1 differentiates its functions by forming either ADAR1 homodimers or Dicer-ADAR1 heterodimers. miRNA expression is globally inhibited in ADAR1-null mouse embryos. |
Co-immunoprecipitation, in vitro Dicer cleavage assay, ADAR1-null mouse embryo analysis |
RNA biology |
Medium |
23949595
|
| 2020 |
ILF3, ILF2, STRBP, and ZFR (DZF-domain-containing proteins) interact with ADAR1 and ADAR2 and modulate RNA editing levels. ILF3 functions as a broadly influential negative regulator of editing. These were identified as trans regulators by BioID proximity labeling followed by mass spectrometry. |
BioID proximity labeling, mass spectrometry, ENCODE data validation, siRNA knockdown of identified interactors with editing level measurement |
Cell reports |
Medium |
32433965
|
| 2024 |
ADAR1 nuclear (p110) and cytoplasmic (p150) isoforms have distinct protein interactomes. Nuclear proteins are stable interactors with both isoforms. ADAR1p110 associates with nuclear components while ADAR1p150 associates with cytoplasmic cellular condensates. dsRNA binding is important for ADAR1 interactions. IFN treatment results in novel interactions, and during IFN response with poly(I:C), ADAR1p150 proximal network associates with antiviral stress granule components. |
Co-IP of endogenous ADAR1, Strep-tag Co-IP, BioID with individual isoforms, RNase A digestion, dsRNA-binding mutant |
Nucleic acids research |
High |
39673305
|
| 2024 |
ADAR1 dsRBD3 forms a stable homodimer, and dimerization disruption via interface mutation does not abrogate editing activity but intricately affects editing efficiency at selected sites, indicating dimerization regulates site specificity rather than global catalytic activity. |
Crystal structure of ADAR1 dsRBD3, interface mutagenesis, in vitro editing assays |
Nature communications |
High |
39572551
|
| 2018 |
The ADAR1 deaminase domain (hADAR1d) has different substrate selectivity from ADAR2. A chimeric protein bearing an RNA-binding loop from hADAR2d grafted onto hADAR1d showed ADAR2-like selectivity, demonstrating that substrate selectivity originates primarily from the deaminase domain RNA-binding loop. High-throughput mutagenesis (Sat-FACS-Seq) identified essential amino acids in an RNA-binding loop of hADAR1d. |
In vitro deamination assays, chimeric domain swap, Sat-FACS-Seq high-throughput mutagenesis |
Biochemistry |
High |
29457714
|
| 2022 |
ADAR1-dependent RNA editing of the 3'-UTR of GM2A (ganglioside catabolism activator) is critical for GBM stem cell self-renewal and stemness. ADAR1 inactivation or JAK/STAT pathway inhibition via TYK2 inhibition impaired GSC self-renewal. ADAR1 and global RNA editomes are elevated in GSCs compared with normal neural stem cells. |
ADAR1 inactivation, TYK2 inhibition, functional assays (self-renewal, stemness), 3'-UTR editing analysis of GM2A |
Journal of Clinical Investigation |
Medium |
35133980
|
| 2021 |
ADAR1 editing-dependent RNA modification of CDK13 coding sequence (c.308A>G) promotes cancer cell hallmarks in thyroid cancer. This editing event increases nucleolar abundance of CDK13 protein and contributes to global changes in splicing produced by ADAR1 deregulation. |
Whole transcriptome sequencing, ADAR1 silencing, cell viability/proliferation/invasion assays, subnuclear localization analysis |
Molecular cancer |
Medium |
34496885
|
| 2022 |
ADAR1-dependent editing of miR-3144-3p at position 3 in the seed region redirects its targeting: edited miR-3144-3p upregulates MSI2 (by no longer suppressing it) and suppresses SLC38A4, contributing to hepatocellular carcinogenesis. |
RNA editing site identification, miRNA mimic transfection, target validation by luciferase/Western, ADAR1 siRNA/KO, mouse tumor model |
Experimental & Molecular Medicine |
Medium |
36599932
|
| 2020 |
ADAR1 editing of dsRNA prevents MDA5 sensing and sequestration of dsRNAs encoding membrane proteins that promote ER homeostasis. Absence of ADAR1-dependent editing induces aberrant innate immune responses through MDA5, unleashing ER stress and hindering epithelial fate acquisition during MET and iPSC reprogramming. The PERK-dependent unfolded protein response pathway is activated downstream. |
ADAR1 KO and chemical inhibition during reprogramming, MDA5 KO rescue, ER stress markers, PERK pathway analysis |
Cell stem cell |
Medium |
32396862
|
| 2023 |
ADAR1 interacts with DHX9 in ovarian cancer cells to regulate R-loop complex formation. Loss of ADAR1 causes R-loop abnormal accumulation, contributing to single-strand DNA breaks and ATR pathway activation. A-to-I editing of nascent RNA by ADAR1 suppresses R-loop formation during co-transcriptional processes. |
Co-immunoprecipitation (ADAR1-DHX9), R-loop detection, ATR activation assays, ADAR1 silencing, cell cycle analysis |
Journal of Cancer |
Medium |
35711824
|
| 2022 |
ADAR1-mediated A-to-I editing globally alters RNA secondary structure in a context-dependent manner. ADAR1 silencing results in a lower global double-stranded to single-stranded RNA ratio, meaning editing can stabilize a large subset of imperfect RNA duplexes (inverted Alus in UTRs). The destabilized duplexes are predominantly cytoplasmic and show higher ribosomal occupancy. |
Parallel analysis of RNA structure sequencing (PARS-seq) in ADAR1-deficient cells |
Nature communications |
Medium |
29129909
|
| 2014 |
ADAR1 p150 is an IFN-inducible isoform found in both cytoplasm and nucleus, while ADAR1 p110 is constitutively expressed and nuclear. ADAR1-dependent A-to-I editing can alter RNA structure stability, mRNA coding, and splicing; inosine is decoded as guanosine by ribosomes and polymerases. |
Isoform characterization via alternative promoter analysis, fractionation, biochemical assays |
Journal of Interferon & Cytokine Research |
Medium |
24905200
|
| 2024 |
Loss of ADAR1 in breast cancer cells induces ferroptosis via a miR-335-5p/Sp1/GPX4 pathway. ADAR1 controls miR-335-5p levels; reduced ADAR1 increases miR-335-5p which targets Sp1, a transcription factor for GPX4, leading to decreased GPX4 and ferroptosis. This function is independent of ADAR1's RNA editing activity. |
CRISPR-Cas9 KO and plasmid overexpression of ADAR1, miR-335-5p measurements, ROS/MDA/GSH/Fe2+ assays, GPX4 protein levels |
Cellular signalling |
Medium |
38866351
|
| 2022 |
ADAR1 prevents autoinflammatory myocarditis in cardiomyocytes via IRF7 as the main mediator. Enzymatic RNA editing activity prevents IRF7-mediated autoinflammatory reactions triggered by endogenous non-edited RNAs via MDA5; additionally ADAR1 serves editing-independent roles required for long-term cardiac function. |
Cardiomyocyte-specific Adar1 KO mice, MDA5 (Ifih1) KO rescue, Irf7 KO rescue, catalytically inactive ADAR1 in Ifih1 mutant background |
Circulation research |
High |
36000401
|
| 2020 |
ADAR1 establishes a negative-feedback loop restricting the viral mimicry response to epigenetic therapy. Intronic and intergenic SINE elements (inverted-repeat Alus) are the major source of drug-induced immunogenic dsRNA. ADAR1 targets and destabilizes inverted-repeat Alu dsRNA, preventing MDA5 receptor activation. Depletion of ADAR1 in patient-derived cancer cells potentiates epigenetic therapy efficacy. |
Epigenetic drug treatment, ADAR1 depletion, dsRNA immunofluorescence, MDA5 activation assays, tumor growth assays |
Nature |
High |
33087935
|
| 2022 |
ADAR1 p150 editing activity prevents MDA5-mediated sensing in cardiomyocytes through its RNA editing activity, while ADAR1 p110 does not contribute to this function. The Zα domain-Z-RNA interaction is required for p150 editing specificity at certain sites critical for preventing MDA5 activation. |
Isoform-specific mouse mutants, MDA5 (Ifih1) KO rescue, Zα domain point mutation (W197A) |
International journal of molecular sciences |
Medium |
34768866
|
| 2023 |
ADAR1-mediated editing of miR-376b-3p in the seed region redirects its target mRNAs to include 4-aminobutyrate aminotransferase (ABAT), the enzyme for GABA catabolism. Edited miR-376b-3p expression increases intracellular GABA levels and cell surface GABA type A receptors. ADAR2 negatively regulates miR-376b-3p maturation in an editing-independent manner. |
ADAR1/ADAR2 editing analysis of miRNA precursors and mature forms, miRNA target prediction and validation, GABA measurement, GABA-A receptor surface expression |
Journal of Biological Chemistry |
Medium |
35124003
|
| 2020 |
ADAR1 requires RNA editing activity to regulate early thymocyte development in part through MDA5 (concurrent MDA5 deletion ameliorated apoptosis but did not restore impaired transition and TCR expression), indicating RNA-editing-dependent and -independent functions of ADAR1 synergistically regulate early thymocyte development. |
Early thymocyte-specific ADAR1 conditional KO, MDA5 KO rescue, forced TCR expression rescue experiments |
Journal of Immunology |
Medium |
32169840
|