Overexpression of ADAR1 in mice does not initiate or accelerate cancer formation in vivo I.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221626 | GEO | 2023/04/28
REPOSITORIES: GEO
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Project description:RNAseq analysis of cell lines with ADAR1-p150 and ADAR1-p110 knock-outs and primary human tissue samples (from GSE57353 and GSE99392 data sets) to identify sites of ADAR1 editing
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Project description:Adenosine deaminase acting on RNA (ADAR) (also known as ADAR1) promotes A-to-I conversion in double-stranded and highly structured RNAs. ADAR1 has two isoforms transcribed from different promoters: ADAR1p150, which is mainly cytoplasmic and interferon-inducible, and constitutively expressed ADAR1p110 that is primarily localized in the nucleus. Mutations in ADAR1 cause Aicardi – Goutières syndrome (AGS), a severe autoinflammatory disease in humans associated with aberrant IFN production. In mice, deletion of ADAR1 or selective knockout of the p150 isoform alone leads to embryonic lethality driven by overexpression of interferon-stimulated genes. This phenotype can be rescued by concurrent deletion of cytoplasmic dsRNA-sensor MDA5. These findings indicate that the interferon-inducible p150 isoform is indispensable and cannot be rescued by the ADAR1p110 isoform. Nevertheless, editing sites uniquely targeted by ADAR1p150 but also mechanisms of isoform- specificity remain elusive. To examine in vivo interaction between ADAR1-isoforms and its substrates, we performed RNA immunoprecipitation and sequencing (RIP-seq) in HEK293 cells. RIP-seq experiment was done with overexpressed flag-tagged ADAR1 isoforms.
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Project description:To inhibitors for ADAR1 and a strong rationale for the development of ADAR1 p150 inhibitors for cancer immunotherapy Here, we describe AVA-ADR-001, a potential first-in-class small molecule inhibitor of ADAR1 p150 targeting the Z alpha domain. AVA-ADR-001 binds specifically to the Z alpha domain of ADAR1 p150 as confirmed by fluorescence spectroscopy and showed significant interferon induction in THP1 macrophages, which have high ADAR1 p150 expression compared with monocytes. Proteomics and transcriptomics analysis revealed significant upregulation of interferon signaling upon treatment with AVA-ADR -001. Interestingly, activation of interferon signaling resulted in AVA-ADR-001 induced cell killing in ADAR1-independent cell lines. In addition, treatment with AVA-ADR -001 resulted in significant activation of PKR, which may explain the decreased cell proliferation. Finally, AVA-ADR-001 showed superior anti-tumor efficacy compared to anti-PD1 in an in vivo tumor efficacy study and has a moderately synergistic effect when combined. Overall, this study reveals that ADAR1 p150 inhibition by AVA-ADR-001 exerts a multipronged impact on anti-tumor efficacy mediated by immune cells, accumulation of interferons and activation of PKR, resulting in protein translation inhibition and cell proliferation arrest.
2023-04-17 | GSE229503 | GEO
Project description:Adenosine deaminase acting on RNA (ADAR) (also known as ADAR1) promotes A-to-I conversion in double-stranded and highly structured RNAs. ADAR1 has two isoforms transcribed from different promoters: ADAR1p150, which is mainly cytoplasmic and interferon-inducible, and constitutively expressed ADAR1p110 that is primarily localized in the nucleus. Mutations in ADAR1 cause Aicardi – Goutières syndrome (AGS), a severe autoinflammatory disease in humans associated with aberrant IFN production. In mice, deletion of ADAR1 or selective knockout of the p150 isoform alone leads to embryonic lethality driven by overexpression of interferon-stimulated genes. This phenotype can be rescued by concurrent deletion of cytoplasmic dsRNA-sensor MDA5. These findings indicate that the interferon-inducible p150 isoform is indispensable and cannot be rescued by the ADAR1p110 isoform. Nevertheless, editing sites uniquely targeted by ADAR1p150 but also mechanisms of isoform- specificity remain elusive. To identify ADAR1 isoform-specific ‘editome’, we transfected A-to-I editing deficient mouse embryonic fibroblasts (MEFs) with ADAR1p150- or ADAR1p110- or RFP-editing negative control. We subjected the samples to RNA sequencing and detected editing at known-editing sites.
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Project description:The ADAR RNA editing enzymes deaminate adenosine bases to inosines in cellular RNAs, recoding open reading frames. Human ADAR1 mutations cause Aicardi-Goutieres Syndrome (AGS) and Adar1 mutant mice showing an aberrant interferon response and death by embryonic day E12.5 model the human disease. Searches have not identified key ADAR1 RNA editing sites recoding immune/haematopoietic proteins but editing is widespread in Alu sequences. We show that Adar1 embryonic lethality is rescued in Adar1; Mavs double mutant mice in which general antiviral responses to cytoplasmic dsRNA are prevented. We propose that inosine bases are epigenetic marks identifying cellular RNA as innate immune ÒselfÓ. Consistent with this idea we show that an editing-active cytoplasmic ADAR is required to prevent aberrant immune responses in Adar1 mutant mouse embryo fibroblasts. No dramatic increase in repetitive transcripts is observed. AGS mutations in ADAR1 affect editing by the interferon-inducible cytoplasmic ADAR1 isoform. RNA-seq expression profiling in Adar1 and Adar1/Mavs knockout mice embryos.
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Project description:Sensing of double-stranded RNA (dsRNA) is an important component of innate immunity. Proteins like PKR and MDA5 recognize dsRNA and activate various pathways to fight viral infection. In addition to viral dsRNA, many endogenous RNAs containing double-stranded regions can be misrecognized as immunogenic. The RNA editing enzyme ADAR1, specifically its p150 isoform, has been shown to suppress activation of PKR and MDA5 through its A-to-I editing activity. While the cytoplasmic ADAR1-p150 isoform has been well established within this role, the functions of the nuclear ADAR1-p110 isoform are less understood. To address this knowledge gap, we utilized proximity labeling by APEX2 to identify putative ADAR1-p110 interacting proteins. We identified 110 proteins across three breast cancer cell lines that either interact with p110 or are within close proximity. Many of these proteins have known roles in RNA metabolism. Nine of the identified proteins belong to the DEAD or DEAH box families of RNA helicases, including DHX9. DHX9 is overexpressed in breast cancer, with expression closely correlated with that of p110. By co-immunoprecipitation we confirmed that p110 interacts with DHX9. Knockdown of DHX9 in several triple-negative breast cancer cell lines caused cell death and activation of the dsRNA sensor PKR. In two cell lines that are refractory to knockdown of ADAR1, the combined knockdown of DHX9 and ADAR1 caused a substantial increase in PKR activity, where knockdown of either alone had no effect. Knockdown of DHX9 and ADAR1 caused activation of the type I IFN pathway, RNase L and NF-KB signaling. Activation of these proteins and pathways was not seen with individual knockdown of ADAR1 or DHX9. Activation of PKR following combined knockdown of ADAR1 and DHX9 could be rescued by expression of p110, p150, DHX9, and catalytically inactive DHX9. Additionally PKR activation could be rescued by the dsRBM of DHX9, revealing an important role for dsRBMs in suppressing PKR activation. Together these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways.
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Project description:The ADAR RNA editing enzymes deaminate adenosine bases to inosines in cellular RNAs, recoding open reading frames. Human ADAR1 mutations cause Aicardi-Goutieres Syndrome (AGS) and Adar1 mutant mice showing an aberrant interferon response and death by embryonic day E12.5 model the human disease. Searches have not identified key ADAR1 RNA editing sites recoding immune/haematopoietic proteins but editing is widespread in Alu sequences. We show that Adar1 embryonic lethality is rescued in Adar1; Mavs double mutant mice in which general antiviral responses to cytoplasmic dsRNA are prevented. We propose that inosine bases are epigenetic marks identifying cellular RNA as innate immune ÒselfÓ. Consistent with this idea we show that an editing-active cytoplasmic ADAR is required to prevent aberrant immune responses in Adar1 mutant mouse embryo fibroblasts. No dramatic increase in repetitive transcripts is observed. AGS mutations in ADAR1 affect editing by the interferon-inducible cytoplasmic ADAR1 isoform.
2014-12-19 | GSE62917 | GEO