ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay

Both p150 and p110 isoforms of ADAR1 convert adenosine to inosine in double-stranded RNA (dsRNA). ADAR1p150 suppresses the dsRNA-sensing mechanism that activates MDA5–MAVS–IFN signaling in the cytoplasm. In contrast, the biological function of the ADAR1p110 isoform, which is usually located in the nucleus, is largely unknown. Here, we show that stress-activated phosphorylation of ADAR1p110 by MKK6–p38–MSK MAP kinases promotes its binding to Exportin-5 and its export from the nucleus. After translocating to the cytoplasm, ADAR1p110 suppresses apoptosis in stressed cells by protecting many antiapoptotic gene transcripts that contain 3′-untranslated-region dsRNA structures primarily comprising inverted Alu repeats. ADAR1p110 competitively inhibits binding of Staufen1 to the 3′-untranslated-region dsRNAs and antagonizes Staufen1-mediated mRNA decay. Our study reveals a new stress-response mechanism in which human ADAR1p110 and Staufen1 regulate surveillance of a set of mRNAs required for survival of stressed cells.

• Publication year

  2017

• Venue

  Nature Structural &Molecular Biology

• Publication date

  2017-03-29

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/nsmb.3403PMID 28436945PMCID 5461201
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A-to-I editing of coding and non-coding RNAs by ADARs

  2015cited by this paper
• The Phyre2 web portal for protein modeling, prediction and analysis

  2015cited by this paper
• Dynamic profiling of double-stranded RNA binding proteins

  2015cited by this paper
• RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself

  2015cited by this paper
• New Insights into the Biological Role of Mammalian ADARs; the RNA Editing Proteins

  2015cited by this paper
• Isoforms of RNA-Editing Enzyme ADAR1 Independently Control Nucleic Acid Sensor MDA5-Driven Autoimmunity and Multi-organ Development.

  2015cited by this paper
• Functional signature for the recognition of specific target mRNAs by human Staufen1 protein

  2014cited by this paper
• The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA

  2014cited by this paper
• Genome-wide analysis of Alu editability

  2014cited by this paper
• Antagonistic and stimulative roles of ADAR1 in RNA silencing

  2013cited by this paper
• ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing.

  2013cited by this paper
• mRNA–mRNA duplexes that auto-elicit Staufen1-mediated mRNA decay

  2013cited by this paper
• Staufen1 senses overall transcript secondary structure to regulate translation

  2013cited by this paper
• Staufen1 dimerizes via a conserved motif and a degenerate dsRNA-binding domain to promote mRNA decay

  2013cited by this paper
• STAU1 binding 3' UTR IRAlus complements nuclear retention to protect cells from PKR-mediated translational shutdown.

  2013cited by this paper
• Proteins that contain a functional Z-DNA-binding domain localize to cytoplasmic stress granules

  2013cited by this paper
• Human TNRC6A is an Argonaute-navigator protein for microRNA-mediated gene silencing in the nucleus.

  2013cited by this paper
• Staufen‐mediated mRNA decay

  2013cited by this paper
• The ADAR protein family

  2012cited by this paper
• Editing of neurotransmitter receptor and ion channel RNAs in the nervous system.

  2012cited by this paper
• Regulation of cytoplasmic mRNA decay

  2012cited by this paper
• Analysis of miRNA expression under stress in Arabidopsis thaliana.

  2012cited by this paper
• Accurate identification of human Alu and non-Alu RNA editing sites

  2012cited by this paper
• Ways and means of eukaryotic mRNA decay.

  2012cited by this paper
• Map2k4 Functions as a Tumor Suppressor in Lung Adenocarcinoma and Inhibits Tumor Cell Invasion by Decreasing Peroxisome Proliferator-Activated Receptor γ2 Expression

  2011cited by this paper
• RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome

  2011cited by this paper
• lncRNAs transactivate Staufen1-mediated mRNA decay by duplexing with 3'UTRs via Alu elements

  2010cited by this paper
• The solution structure of the ADAR2 dsRBM-RNA complex reveals a sequence-specific readout of the minor groove.

  2010cited by this paper
• Mechanisms and functions of p38 MAPK signalling.

  2010cited by this paper
• dsRNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis

  2010cited by this paper
• RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis

  2010cited by this paper
• Post-transcriptional regulons coordinate the initiation and resolution of inflammation

  2010cited by this paper
• p38(MAPK): stress responses from molecular mechanisms to therapeutics.

  2009cited by this paper
• The Sequence Alignment/Map format and SAMtools

  2009cited by this paper
• edgeR: a Bioconductor package for differential expression analysis of digital gene expression data

  2009cited by this paper
• Nuclear Localization of p38 MAPK in Response to DNA Damage

  2009cited by this paper
• RNA-Regulated Interaction of Transportin-1 and Exportin-5 with the Double-Stranded RNA-Binding Domain Regulates Nucleocytoplasmic Shuttling of ADAR1

  2009cited by this paper
• ADAR1 is essential for maintenance of hematopoiesis and suppression of interferon signaling

  2008cited by this paper
• Non-Classical P38 Map Kinase Functions: Cell Cycle Checkpoints and Survival

  2008cited by this paper
• MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification

  2008cited by this paper
• Redirection of Silencing Targets by Adenosine-to-Inosine Editing of miRNAs

  2007cited by this paper
• Reading protein modifications with interaction domains

  2006cited by this paper
• Modulation of microRNA processing and expression through RNA editing by ADAR deaminases

  2006cited by this paper
• Mammalian Staufen1 recruits Upf1 to specific mRNA 3'UTRs so as to elicit mRNA decay.

  2005cited by this paper
• Activation and signaling of the p38 MAP kinase pathway

  2005cited by this paper
• Stress-induced Apoptosis Associated with Null Mutation of ADAR1 RNA Editing Deaminase Gene*

  2004cited by this paper
• Computational identification of plant microRNAs and their targets, including a stress-induced miRNA.

  2004cited by this paper
• Liver Disintegration in the Mouse Embryo Caused by Deficiency in the RNA-editing Enzyme ADAR1*

  2004cited by this paper
• Mitogen-activated protein kinases in apoptosis regulation

  2004cited by this paper
• Minihelix-containing RNAs Mediate Exportin-5-dependent Nuclear Export of the Double-stranded RNA-binding Protein ILF3*

  2004cited by this paper
• Requirement of Dimerization for RNA Editing Activity of Adenosine Deaminases Acting on RNA*

  2003cited by this paper
• Reversible cross-linking combined with immunoprecipitation to study RNA-protein interactions in vivo.

  2002cited by this paper
• The PyMOL Molecular Graphics System

  2002cited by this paper
• Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins

  2002cited by this paper
• Formation of higher-order nuclear Rad51 structures is functionally linked to p21 expression and protection from DNA damage-induced apoptosis.

  2002cited by this paper
• SB203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance.

  2001cited by this paper
• Constitutive Activation of Extracellular Signal-regulated Kinase 2 by Synergistic Point Mutations*

  2001cited by this paper
• Protective roles for ATM in cellular response to oxidative stress

  2000cited by this paper
• Functionally Distinct Double-stranded RNA-binding Domains Associated with Alternative Splice Site Variants of the Interferon-inducible Double-stranded RNA-specific Adenosine Deaminase*

  1997cited by this paper
• MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway

  1996cited by this paper
• A novel receptor-mediated nuclear protein import pathway.

  1996cited by this paper
• Mutagenic Analysis of Double-stranded RNA Adenosine Deaminase, a Candidate Enzyme for RNA Editing of Glutamate-gated Ion Channel Transcripts (*)

  1995cited by this paper
• Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase

  1995cited by this paper
• A double-stranded RNA unwinding activity introduces structural alterations by means of adenosine to inosine conversions in mammalian cells and Xenopus eggs.

  1989cited by this paper
• Electronic Reprint Biological Crystallography Phenix : a Comprehensive Python-based System for Macromolecular Structure Solution

  year unknowncited by this paper

• Identification of ADAR1i-124: The first effective A-to-I RNA editing inhibitor with promising cancer therapeutic potential

  2026cites this paper
• ADAR1 upregulates the translation of cytochrome c via the inhibition of translocation into stress granules, facilitating apoptosis by an anticancer agent.

  2026cites this paper
• RNA editing: an emerging frontier in cancer therapy - explorations, opportunities, and challenges.

  2026cites this paper
• Stereo-random oligonucleotides enable efficient recruitment of ADAR in vitro and in vivo

  2025cites this paper
• A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system

  2025cites this paper
• ADAR1p110 promotes hepatocellular carcinoma metastasis via the miR-451a/TUBA1A axis

  2025cites this paper
• Double-stranded RNA adenosine deaminases suppress ferroptosis through regulating SCD1.

  2025cites this paper
• ADARp110 promotes hepatocellular carcinoma progression via stabilization of CD24 mRNA

  2025cites this paper
• Targeting RNA Adenosine Editing and Modification Enzymes for RNA therapeutics.

  2025cites this paper
• A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases

  2025cites this paper
• Unveiling RNA Editing by ADAR and APOBEC Protein Gene Families.

  2025cites this paper
• Editing specificity of ADAR isoforms.

  2025cites this paper
• Endothelial ADAR1 Deficit Induces the NOCT-IRF7 Axis in Pulmonary Hypertension.

  2025cites this paper
• Epitranscriptome-wide profiling identifies RNA editing events regulated by ADAR1 that are associated with DNA repair mechanisms in human TK6 cells

  2025cites this paper
• Distinct interactomes of ADAR1 nuclear and cytoplasmic protein isoforms and their responses to interferon induction

  2024cites this paper
• ADAR1 expression in different cancer cell lines and its change under heat shock

  2024cites this paper
• Viral N protein hijacks deaminase-containing RNA granules to enhance SARS-CoV-2 mutagenesis

  2024cites this paper
• ADAR3 modulates neuronal differentiation and regulates mRNA stability and translation

  2024cites this paper
• Adenosine-to-inosine RNA editing in cancer: molecular mechanisms and downstream targets

  2024cites this paper
• Spatial visualization of A-to-I Editing in cells using Endonuclease V Immunostaining Assay (EndoVIA)

  2024cites this paper
• ADAR-Mediated A>I(G) RNA Editing in the Genotoxic Drug Response of Breast Cancer

  2024cites this paper
• Inverted Alu repeats: friends or foes in the human transcriptome

  2024cites this paper
• Loss of ADAR1 protein induces changes in small RNA landscape in hepatocytes

  2024cites this paper
• MEF2C Directly Interacts with Pre-miRNAs and Distinct RNPs to Post-Transcriptionally Regulate miR-23a-miR-27a-miR-24-2 microRNA Cluster Member Expression

  2024cites this paper
• Nuclear aggregates of NONO/SFPQ and A-to-I-edited RNA in Parkinson's disease and dementia with Lewy bodies.

  2024cites this paper
• Multi-System-Level Analysis with RNA-Seq on Pterygium Inflammation Discovers Association between Inflammatory Responses, Oxidative Stress, and Oxidative Phosphorylation

  2024cites this paper
• Spatial Visualization of A-to-I Editing in Cells Using Endonuclease V Immunostaining Assay (EndoVIA)

  2024cites this paper
• To initiate or not to initiate: A critical assessment of eIF2A, eIF2D, and MCT-1·DENR to deliver initiator tRNA to ribosomes

  2024cites this paper
• Malignant A-to-I RNA editing by ADAR1 drives T cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing

  2024cites this paper
• The role of ADAR1 through and beyond its editing activity in cancer

  2024cites this paper
• Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells

  2024cites this paper
• Emerging role of the RNA-editing enzyme ADAR1 in stem cell fate and function

  2023cites this paper
• ADAR1 polymorphisms contribute to increased susceptibility in pediatric acute lymphoblastic leukemia

  2023cites this paper
• The cellular and KSHV A-to-I RNA editome in primary effusion lymphoma and its role in the viral lifecycle

  2023cites this paper
• The competitive landscape of the dsRNA world.

  2023cites this paper
• Increased levels of eIF2A inhibit translation by sequestering 40S ribosomal subunits

  2023influential citation
• ADAR1 links R-loop homeostasis to ATR activation in replication stress response

  2023cites this paper
• Harnessing ADAR-Mediated Site-Specific RNA Editing in Immune-Related Disease: Prediction and Therapeutic Implications

  2023cites this paper
• Induction of viral mimicry upon loss of DHX9 and ADAR1 in breast cancer cells

  2023cites this paper
• ADAR1 exacerbates ischemic brain injury via astrocyte-mediated neuron apoptosis

  2023cites this paper
• Alternative Splicing, RNA Editing, and the Current Limits of Next Generation Sequencing

  2023cites this paper
• ADAD1 is required for normal translation of nuclear pore and transport protein transcripts in spermatids of Mus musculus

  2023cites this paper
• ADAR1-Mediated RNA Editing and Its Role in Cancer

  2022cites this paper
• Phosphomimicry on STAU1 Serine 20 Impairs STAU1 Posttranscriptional Functions and Induces Apoptosis in Human Transformed Cells

  2022cites this paper
• RNA editing enzyme ADAR1 controls miR-381-3p-mediated expression of multidrug resistance protein MRP4 via regulation of circRNA in human renal cells

  2022cites this paper
• Interplay between A-to-I Editing and Splicing of RNA: A Potential Point of Application for Cancer Therapy

  2022influential citation
• ADAR1 and its implications in cancer development and treatment.

  2022cites this paper
• The E3 ubiquitin ligase SMURF2 stabilizes RNA editase ADAR1p110 and promotes its adenosine-to-inosine (A-to-I) editing function

  2022cites this paper
• Increase in ADAR1p110 activates the canonical Wnt signaling pathway associated with aggressive phenotype in triple negative breast cancer cells.

  2022cites this paper
• Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium

  2022cites this paper
• Exploring the lncRNA localization landscape within the retinal pigment epithelium under normal and stress conditions

  2022cites this paper
• RNA modifications in cardiovascular health and disease

  2022cites this paper
• Karyopherin-mediated nucleocytoplasmic transport

  2022cites this paper
• Granulosa Cell Specific Loss of Adar in Mice Delays Ovulation, Oocyte Maturation and Leads to Infertility

  2022cites this paper
• Endogenous retroelements as alarms for disruptions to cellular homeostasis.

  2022cites this paper
• Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis

  2022cites this paper
• Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases

  2022cites this paper
• ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation

  2022cites this paper
• ADAR1 downregulation by autophagy drives senescence independently of RNA editing by enhancing p16INK4a levels

  2022cites this paper
• RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS

  2022influential citation
• Proline‐arginine poly‐dipeptide encoded by the C9orf72 repeat expansion inhibits adenosine deaminase acting on RNA

  2021cites this paper
• CASC5 Gene Expression Changes Correlate with Targeted Mutations in Leukemia

  2021cites this paper
• The Regulation of RNA Modification Systems: The Next Frontier in Epitranscriptomics?

  2021cites this paper
• Endogenous Double-Stranded RNA

  2021cites this paper
• Decoupling expression and editing preferences of ADAR1 p150 and p110 isoforms

  2021cites this paper
• RNA editing enzyme ADAR1 governs the circadian expression of P-glycoprotein in human renal cells by regulating alternative splicing of the ABCB1 gene

  2021cites this paper
• Adenosine Deaminases Acting on RNA (ADARs) and Viral Infections.

  2021cites this paper
• RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain

  2021cites this paper
• To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

  2021cites this paper
• The Staufen1‐dependent cell cycle regulon or how a misregulated RNA‐binding protein leads to cancer

  2021cites this paper
• The role of RNA editing enzyme ADAR1 in human disease

  2021cites this paper
• Adenosine-to-Inosine RNA Editing: A Key RNA Processing Step Rewriting Transcriptome in Normal Physiology and Diseases

  2021cites this paper
• Double-stranded RNA-specific adenosine deaminase-knockdown inhibits the proliferation and induces apoptosis of DU145 and PC3 cells by promoting the phosphorylation of H2A.X variant histone

  2021cites this paper
• Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis.

  2021cites this paper
• Detection of A-to-I RNA Editing in SARS-COV-2

  2021cites this paper
• High Level of Staufen1 Expression Confers Longer Recurrence Free Survival to Non-Small Cell Lung Cancer Patients by Promoting THBS1 mRNA Degradation

  2021cites this paper
• Novel Insights into the Role of UBE3A in Regulating Apoptosis and Proliferation

  2020cites this paper
• Immune-related IncRNA LINC00944 responds to variations in ADAR1 levels and it is associated with breast cancer prognosis.

  2020cites this paper
• ADARs, RNA editing and more in hematological malignancies

  2020cites this paper
• Epigenetic Control of circHNRNPH1 in Postischemic Myocardial Fibrosis through Targeting of TGF-β Receptor Type I

  2020cites this paper
• Evaluating the therapeutic potential of ADAR1 inhibition for triple-negative breast cancer

  2020cites this paper
• RNA editing in mesothelioma: a look forward

  2020cites this paper
• Processing of Alu small RNAs by DICER/ADAR1 complexes and their RNAi targets

  2020influential citation
• Prevention of dsRNA‐induced interferon signaling by AGO1x is linked to breast cancer cell proliferation

  2020cites this paper
• 3′READS + RIP defines differential Staufen1 binding to alternative 3′UTR isoforms and reveals structures and sequence motifs influencing binding and polysome association

  2020cites this paper
• ADAD1 and ADAD2, testis-specific adenosine deaminase domain-containing proteins, are required for male fertility

  2020cites this paper
• Staufen1 localizes to the mitotic spindle and controls the localization of RNA populations to the spindle

  2020cites this paper
• ALU non-B-DNA conformations, flipons, binary codes and evolution

  2020cites this paper
• Role of ANKHD1/LINC00346/ZNF655 Feedback Loop in Regulating the Glioma Angiogenesis via Staufen1-Mediated mRNA Decay

  2020cites this paper
• ADAR1 Prevents R-loop Accumulation-Driven ATR Pathway Activation in Ovarian Cancer

  2020cites this paper
• Decrease in ADAR1 expression by exposure to cigarette smoke enhances susceptibility to oxidative stress.

  2020cites this paper
• NF45 and NF90 Regulate Mitotic Gene Expression by Competing with Staufen-Mediated mRNA Decay.

  2020cites this paper
• Staufen1 is essential for cell cycle transitions and cell proliferation via the control of E2F1 expression.

  2020cites this paper
• ADAR1 Transcriptome editing promotes breast cancer progression through the regulation of cell cycle and DNA damage response.

  2020cites this paper
• Staufen1 localizes to the mitotic spindle and controls the transport of RNA populations to the spindle

  2020cites this paper
• ADAR1 Regulates Early T Cell Development via MDA5-Dependent and -Independent Pathways

  2020cites this paper
• ADAR2 Regulates Malignant Behaviour of Mesothelioma Cells Independent of RNA-editing Activity

  2020cites this paper
• Deletion of Endonuclease V suppresses chemically induced hepatocellular carcinoma

  2020cites this paper
• Short interspersed nuclear element (SINE)-mediated post-transcriptional effects on human and mouse gene expression: SINE-UP for active duty

  2020cites this paper
• Endothelial cell-specific deficiency of the adenosine deaminase ADAR1 aggravates LPS-induced lung injury in mice via an MDA5-independent pathway.

  2020cites this paper