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Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line.

ABSTRACT: ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA reducing its immunostimulatory activities. Mutation of ADAR1 leads to a severe neurodevelopmental and inflammatory disease of children, Aicardi-Goutiéres syndrome. In mice, Adar1 mutations are embryonic lethal but are rescued by mutation of the Mda5 or Mavs genes, which function in IFN induction. However, the specific IFN regulated proteins responsible for the pathogenic effects of ADAR1 mutation are unknown. We show that the cell-lethal phenotype of ADAR1 deletion in human lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of the RNASEL gene or by expression of the RNase L antagonist, murine coronavirus NS2 accessory protein. Our result demonstrate that ablation of RNase L activity promotes survival of ADAR1 deficient cells even in the presence of MDA5 and MAVS, suggesting that the RNase L system is the primary sensor pathway for endogenous dsRNA that leads to cell death.

SUBMITTER: Li Y

PROVIDER: S-EPMC5404912 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Distinct in vivo roles for double-stranded RNA-binding domains of the Xenopus RNA-editing enzyme ADAR1 in chromosomal targeting.

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The editing enzyme ADAR1 and the mRNA surveillance protein hUpf1 interact in the cell nucleus.

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The RNA-editing enzyme ADAR1 controls innate immune responses to RNA.

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Editing of HIV-1 RNA by the double-stranded RNA deaminase ADAR1 stimulates viral infection.

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ADAR1-mediated RNA editing promotes B cell lymphomagenesis.

Project description:Diffuse large B cell lymphoma (DLBCL) is one of the most common types of aggressive lymphoid malignancies. Here, we explore the contribution of RNA editing to DLBCL pathogenesis. We observed that DNA mutations and RNA editing events are often mutually exclusive, suggesting that tumors can modulate pathway outcomes by altering sequences at either the genomic or the transcriptomic level. RNA editing targets transcripts within known disease-driving pathways such as apoptosis, p53 and NF-κB signaling, as well as the RIG-I-like pathway. In this context, we show that ADAR1-mediated editing within MAVS transcript positively correlates with MAVS protein expression levels, associating with increased interferon/NF-κB signaling and T cell exhaustion. Finally, using targeted RNA base editing tools to restore editing within MAVS 3'UTR in ADAR1-deficient cells, we demonstrate that editing is likely to be causal to an increase in downstream signaling in the absence of activation by canonical nucleic acid receptor sensing.

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Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis.

Project description:The introduction of new therapies against particular genetic mutations in non-small-cell lung cancer is a promising avenue for improving patient survival, but the target population is small. There is a need to discover new potential actionable genetic lesions, to which end, non-conventional cancer pathways, such as RNA editing, are worth exploring. Herein we show that the adenosine-to-inosine editing enzyme ADAR1 undergoes gene amplification in non-small cancer cell lines and primary tumors in association with higher levels of the corresponding mRNA and protein. From a growth and invasion standpoint, the depletion of ADAR1 expression in amplified cells reduces their tumorigenic potential in cell culture and mouse models, whereas its overexpression has the opposite effects. From a functional perspective, ADAR1 overexpression enhances the editing frequencies of target transcripts such as NEIL1 and miR-381. In the clinical setting, patients with early-stage lung cancer, but harboring ADAR1 gene amplification, have poor outcomes. Overall, our results indicate a role for ADAR1 as a lung cancer oncogene undergoing gene amplification-associated activation that affects downstream RNA editing patterns and patient prognosis.

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ADAR1 interacts with NF90 through double-stranded RNA and regulates NF90-mediated gene expression independently of RNA editing.

Project description:The RNA-editing enzyme ADAR1 modifies adenosines by deamination and produces A-to-I mutations in mRNA. ADAR1 was recently demonstrated to function in host defense and in embryonic erythropoiesis during fetal liver development. The mechanisms for these phenotypic effects are not yet known. Here we report a novel function of ADAR1 in the regulation of gene expression by interacting with the nuclear factor 90 (NF90) proteins, known regulators that bind the antigen response recognition element (ARRE-2) and have been demonstrated to stimulate transcription and translation. ADAR1 upregulates NF90-mediated gene expression by interacting with the NF90 proteins, including NF110, NF90, and NF45. A knockdown of NF90 with small interfering RNA suppresses this function of ADAR1. Coimmunoprecipitation and double-stranded RNA (dsRNA) digestion demonstrate that ADAR1 is associated with NF110, NF90, and NF45 through the bridge of cellular dsRNA. Studies with ADAR1 deletions demonstrate that the dsRNA binding domain and a region covering the Z-DNA binding domain and the nuclear export signal comprise the complete function of ADAR1 in upregulating NF90-mediated gene expression. These data suggest that ADAR1 has the potential both to change information content through editing of mRNA and to regulate gene expression through interacting with the NF90 family proteins.

| S-EPMC1190226 | biostudies-literature

ADAR1 is required for hematopoietic progenitor cell survival via RNA editing.

Project description:Adenosine Deaminase Acting on RNA 1 (ADAR1) is an RNA-editing enzyme that converts adenosine to inosine, following RNA transcription. ADAR1's essential role in embryonic development, especially within the hematopoietic lineage, has been demonstrated in knock-out mice. However, a specific role for ADAR1 in adult hematopoietic progenitor cells (HPCs) remains elusive. In this report, we show that ADAR1 is required for survival of differentiating HPCs as opposed to more primitive cells in adult mice by multiple strategies targeting floxed ADAR1 for deletion by Cre recombinase. As a consequence, ADAR1-deficient hematopoietic stem cells (HSCs) were incapable of reconstituting irradiated recipients although being phenotypically present in the recipient bone marrow. While an effect on HSCs cannot be completely ruled out, the preferential effect of ADAR1 absence on HPCs over more primitive hematopoietic cells was consistent with the increased expression of ADAR1 within HPCs, as well as the inability of ADAR1-deficient HPCs to form differentiated colonies and increased apoptotic fraction during ex vivo culture. Moreover, we have obtained direct evidence that ADAR1 functions in HPCs via an RNA-editing dependent mechanism. Therefore, ADAR1 plays an essential role in adult hematopoiesis through its RNA editing activity in HPCs.

| S-EPMC2764897 | biostudies-other

A-to-I RNA editing enzyme Adar1 is essential for cardiac morphogenesis

Project description:In recent years, the topic of RNA modifications, epitranscriptomics, has gained momentum in a variety of fields. It is now firmly established that modifications of RNA can affect splicing, RNA stability and turnover, and translation, which ultimately influence the pathophysiology of organisms. Although its importance has been appreciated, epitranscriptomics in the heart has not been investigated extensively. Among over 140 RNA modifications, adenosine-to-inosine (A-to-I) RNA editing is of particular interest in the heart as it is reported to be increased in patients of congenital heart defects and atherosclerosis. However, its function in cardiomyocytes, especially during development, has not been investigated.

2020-05-05 | GSE141345 | GEO

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