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ADAR1 Zα domain P195A mutation activates the MDA-5 dependent RNA-sensing signaling pathway in the brain enhanced by haploinsufficiency without overall RNA editing level decrease.

ABSTRACT: ADAR1 Zα domain P195A mutation activates the MDA-5 dependent RNA-sensing signaling pathway in the brain enhanced by haploinsufficiency without overall RNA editing level decrease.

PROVIDER: PRJNA956522 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24195431_1.fastq.gz	Fastqsanger.gz
	SRR24195431_2.fastq.gz	Fastqsanger.gz
	SRR24195432_1.fastq.gz	Fastqsanger.gz
	SRR24195432_2.fastq.gz	Fastqsanger.gz
	SRR24195433_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

ADAR1 Zα domain P195A mutation activates the MDA-5 dependent RNA-sensing signaling pathway in the brain enhanced by haploinsufficiency without overall RNA editing level decrease.

Project description:The A-to-I RNA editing enzyme ADAR1 critically regulates the cellular RNA sensing signaling pathway, as the RNA-sensing signaling pathway recognizes unedited RNAs as “non-self” to activate the innate immune response. Mutations of ADAR1 cause severe inflammatory tissue injury, as shown in Aicardi-Goutières syndrome (AGS), in which severe inflammation occurs in the brain. The most frequent ADAR1 mutation in AGS is the P193A mutation in the Za domain, which exists in the AGS families coupling with an additional ADAR1 mutation. How this mutation alters the cellular RNAs leading to innate immune activation, has not been fully understood. This study analyzed RNA editing status and innate immune activation in the brains of a mouse model that carries the human ADAR1 P193A-equivalent mouse P195A mutation. We found that this mutation alone can cause excessive ISG expression in the brains, especially in the periventricular areas reflecting the pathologic feature of AGS. Furthermore, we found that ADAR1 P195A mutation did not affect the RNA editing activity in the overall RNA editing level; however, it leads to ISG expression in a dose-dependent manner, causing severer innate immune activation in haploinsufficiency status, whereas wildtype ADAR1 is redundant to suppress innate immune activation. The finding from this study indicated that the intact Z-RNA binding activity of ADAR1 plays a critical role in suppressing self-cellular RNA sensing, and innate immune homeostasis requires a minimum Z-RNA binding capacity of ADAR1.

2023-05-31 | GSE229884 | GEO

ADAR1 regulates melanoma progression via miRNAs biogenesis

Project description:Aberrant RNA-editing was observed in several human tumors, but its significance is mostly unknown. Here we show that ADAR1, a ubiquitous RNA-editing enzyme, is commonly lost in metastatic melanoma cells and specimens. Experimental ADAR1 silencing significantly alters melanoma cell morphology, facilitates proliferation and cell-cycle, and increases the tumorigenicity in-vivo. A series of ADAR1 truncation mutants establishes a novel RNA-editing-independent role for ADAR1 in controlling the nuclear and cytoplasmic processing steps of miRNA biogenesis. Altered expression of ADAR1-controled miRNAs accounts for the observed phenotype. We show that the oncogenic miR-17-5p endogenously regulates ADAR1 expression and that its genomic sequence is frequently amplified in melanoma to overexpress the mature miR-17-5p form. ADAR1 and miR-17-5p are ubiquitously expressed, suggesting the generality of this mechanism. Melanoma cell line expressing low ADAR1 levels (ADAR1-Knockdown) using shRNA technique were selected for RNA extraction and hybridization on Affymetrix microarrays. We sought to examine the alterations in the genes and microRNA expression profile in the manipulated cell system, due to ADAR1 possible involvement cancer development. To that end, we selected ADAR1-knockdown (ADAR1-KD) cells that demonstrated an enhanced aggressive phenotype both in vivo and in vitro as compared to the control cells (Control).

2012-08-31 | E-GEOD-31963 | biostudies-arrayexpress

HCL Overall Analysis

Project description:HCL Overall Analysis

| PRJNA671384 | ENA

ADAR1 overexpression in MDA-MB-231 cells

Project description:ADAR1 overexpression in MDA-MB-231 cells

| PRJNA547525 | ENA

TAB2 haploinsufficiency

Project description:TAB2 haploinsufficiency

| PRJNA747894 | ENA

ADAR1-editing in HeLa, p150-KO and ADAR1-KO transcriptomes

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

2018-12-04 | GSE115127 | GEO

Role of ADAR1 in human macrophages

Project description:This study aims to delineate the role of ADAR1 in human cells beyond its canonical function as an interferon-stimulated gene (ISG). Human monocyte-derived macrophages were subjected to RNA interference targeting either pan-ADAR1 (both isoforms) or the p150 isoform specifically. Quantitative proteomic analyses were performed using state-of-the-art isobaric tandem mass tag (TMT) labeling coupled with liquid chromatography–tandem mass spectrometry (LC-MS/MS). Strikingly, silencing of ADAR1 significantly impacted prototypical macrophage functions, including endocytosis, cholesterol metabolism, and lysosomal processing, without concurrent induction of pro-inflammatory or ISG responses. Pan-ADAR1 silencing resulted in upregulation of proteins involved in lysosomal function and cholesterol processing, whereas selective depletion of ADAR1-p150 led to downregulation of pathways associated with phagocytosis and endocytosis. Moreover, loss of pan-ADAR1 caused a marked downregulation of cell-cycle and p53 signaling pathways, suggesting a potential role for the ADAR1-p110 isoform in regulating cell proliferation. Collectively, these data define previously unappreciated proteomic alterations driven by ADAR1 that influence fundamental macrophage functions beyond its established ISG role.

2026-02-13 | PXD073582 | Pride

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

Project description:Leukemia initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches to eliminate LICs and prevent relapse. Here, we show that the RNA editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine (A-to-I) editing is a common attribute of relapsed T-ALL regardless of molecular subtypes. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL PDX models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA to avoid detection by the innate immune sensor MDA5. Moreover, we uncovered that the cell intrinsic level of MDA5 dictates the dependency on ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents an effective therapeutic strategy for eliminating T-ALL LICs.

2023-12-31 | GSE221112 | GEO

ADAR1 RNA editing regulates endothelial cell functions via the MDA-5 RNA sensing signaling pathway.

Project description: Not available

| S-EPMC8739526 | biostudies-literature

Identification of ADAR1 associated proteins

Project description:To understand how ADAR1 controls genome stability, affinity purification and mass spectrometry were employed to identify the interactomes of ADAR1 with cellular extracts from HeLa cells stably expressing FLAG-ADAR1.Mass spectrometry analysis of FLAG-ADAR1 associated proteins. The differential protein bands of the immunoprecipitates from cellular extracts of HeLa cells were retrieved from silver stained SDS-PAGE, digested with trypsin and analyzed by mass spectrometry.

2022-11-15 | PXD038167 |

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