ADAR1: A New Target for Immuno-oncology Therapy

Bhate, Amruta; Sun, Tao; Li, Jin Billy

doi:10.1016/j.molcel.2019.02.021

Cited by 58 publications

(47 citation statements)

References 14 publications

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“…These editing events have been shown to play a role in self versus non-self RNA recognition in the innate immune response, and thus dysregulation of ADAR1 leads to immune-related diseases such as Aicardi-Goutieres syndrome (AGS) (Blango and Bass, 2016; Liddicoat et al, 2015; Mannion et al, 2014; Pestal et al, 2015; Rice et al, 2012). ADAR1 levels also correlate with tumor aggressiveness, as increases in ADAR1 editing suppress the innate immune response in tumors; accordingly, ADAR1 ablation helps with cancer therapy (Bhate et al, 2019; Gannon et al, 2018; Ishizuka et al, 2019; Liu et al, 2019; Nemlich et al, 2018). While the majority of ADAR1-regulated editing sites are found in repeat regions, ADAR2 is primarily responsible for editing adenosines found in non-repeat regions, particularly in the brain (Tan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Freund

Sapiro

et al. 2019

Preprint

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13Adenosine-to-Inosine RNA editing is catalyzed by ADAR enzymes that deaminate adenosine to 14 inosine. While many RNA editing sites are known, few trans regulators have been identified. We 15 perform BioID followed by mass-spectrometry to identify trans regulators of ADAR1 and ADAR2 16 in HeLa and M17 neuroblastoma cells. We identify known and novel ADAR-interacting proteins. 17Using ENCODE data we validate and characterize a subset of the novel interactors as global or 18 site-specific RNA editing regulators. Our set of novel trans regulators includes all four members 19 of the DZF-domain-containing family of proteins: ILF3, ILF2, STRBP, and ZFR. We show that 20 these proteins interact with each ADAR and modulate RNA editing levels. We find ILF3 is a 21 global negative regulator of editing. This work demonstrates the broad roles RNA binding 22 proteins play in regulating editing levels and establishes DZF-domain containing proteins as a 23 group of highly influential RNA editing regulators. 24 25 47 the majority of ADAR1-regulated editing sites are found in repeat regions, ADAR2 is primarily 48 responsible for editing adenosines found in non-repeat regions, particularly in the brain (Tan et 49 al., 2017). ADAR2-regulated sites in non-repetitive regions include a number of editing events 50 that alter the protein-coding sequences of neuronal RNAs, including GluR2, which encodes a 51 glutamate receptor in which RNA editing is necessary for its proper function. Further 52 demonstrating its important role in neuronal editing, dysregulation of human ADAR2 is 53 associated with multiple neurological diseases, including amyotrophic lateral sclerosis, 54 astrocytoma and transient forebrain ischemia (Slotkin and Nishikura, 2013; Tran et al., 2019). 55Maintaining RNA editing levels is critical for human health, but how RNA editing levels are 56 regulated at specific editing sites across tissues and development is poorly understood. 58While RNA sequence and structure are critical determinants of editing levels, studies querying 59 tissue-specific and developmental-stage-specific editing levels show that the level of editing at 60 the same editing site can vary greatly between individuals and tissues. These changes do not 61 always correlate with ADAR mRNA or protein expression, suggesting a complex regulation of 62 editing events by factors other than ADAR proteins (Sapiro et al., 2019; Tan et al., 2017; 63 Wahlstedt et al., 2009). Recently, an analysis of proteins with an RNA-binding domain profiled 64 by ENCODE suggested that RNA-binding proteins play a role in RNA editing regulation. Further, 65 in mammals, a small number of trans regulators of editing have been identified through 66 functional experiments (Quinones-Valdez et al., 2019). Some of these trans regulators of editing 67 are site-specific, in that they affect editing levels at only a small subset of editing sites. These 68 include RNA binding proteins such as DHX15, HNRNPA2/B1, RPS14, TDP-43, Drosha and 69 Ro60 (Garncarz et al., 2013; Quinones-Valdez ...

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Section: Introductionmentioning

confidence: 99%

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Freund

Sapiro

et al. 2019

Preprint

Self Cite

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“…As ADAR1 peaks are relatively broad in intergenic regions and RNA editing sites are rarely fully edited, there could be a hint that ADAR1 might target a subset of transcriptional byproducts escaped from earlier RNA degradation. As long unedited endogenous dsRNAs could trigger viral immune response, ADAR1 has become an emerging target of cancer immunotherapy (16,17). Thus, this type of transcriptional byproducts may be of clinical values and should not be overlooked.…”

Section: Discussionmentioning

confidence: 99%

Widespread interaction between ADAR1 and transcriptional byproducts

Tang

Tan

et al. 2019

Preprint

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Background: ADAR1, an adenosine-to-inosine (A-to-I) RNA editing enzyme, has an emerging role in cancer immunotherapy. ADAR1 presumably works by suppressing cellular innate immunity response to endogenously generated double-stranded RNAs through RNA editing. However, RNA species that are directly regulated by ADAR1 mediated RNA editing processes remain poorly defined. Results:In this study, we used a novel bioinformatics approach to track ADAR1-RNA interactions. By integrating DNA-seq, RNA-seq, and ADAR1 RNA immunoprecipitation sequencing (fRIP-seq) data of K562 cell line, we provided the first in-situ landscape profiling of ADAR1 RNA binding and editing activities. With long RNA fragments captured by ADAR1 immunoprecipitation, we were able to identify exon junctions and genomic boundaries used by ADAR1-associated RNAs and thus we could possibly trace pre-RNA processing steps that had been acting on them. Our methodology allowed us to establish the knowledge of transcriptome-wide scenario of ADAR1 activities. Intriguingly, we found that ADAR1 had a tendency to interact with transcriptional byproducts originated from obscure regions such as introns and intergenic regions. Conclusions:Our observation might shed light on the dual role of ADAR1 proteins not only in diversifying the transcriptome, but also in reigning RNA debris from obscure regions. Moreover, as the functional potential of seemly transcriptional byproducts is just beginning to emerge, this study would bridge ADAR1 with other fields of RNA biology.

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“…However, in mammals, most A-to-I edits occur in noncoding regions, particularly within the SINE family of retrotransposons that form long double-stranded RNAs; ADAR1 is the main enzyme responsible for editing these duplicates [5]. In tumor therapy, loss of ADAR1 function in tumor cells removes a checkpoint that normally restrains sensing of interferon-inducible double-stranded RNA, leading to enhanced tumor inflammation and heightened interferon sensitivity [6].…”

Section: Introductionmentioning

confidence: 99%

“…ADAR1 can bind to Dicer, improve its cutting efficiency, and promote the production of mature miRNAs. ADAR1 can also perform A-to-I editing of pri-miRNAs to reduce the generation of corresponding mature miRNAs [5]. In viral myocarditis, ADAR1 p150 plays a key role in complexing with Dicer and promoting the expression of miRNA-222, the latter of which suppresses the expression of the target gene phosphatase-and-tensin (PTEN), which acts as a mediator of several cellular events including apoptosis, cell survival, proliferation, and migration [33].…”

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confidence: 99%

ADAR1 Alleviates Inflammation in a Murine Sepsis Model via the ADAR1-miR-30a-SOCS3 Axis

Zhou

Liu

Zhao

et al. 2020

Mediators of Inflammation

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Adenosine deaminase acting on double-stranded RNA 1 (ADAR1) mediates adenosine-to-inosine (A-to-I) RNA editing events. ADAR1 is highly expressed in “septic” macrophages and in small intestinal tissues of mice with sepsis. Overexpression of ADAR1 suppresses inflammation and intestinal damage. However, the specific underlying mechanism is unclear. This study was conducted to explore how microRNA (miRNA) regulates the anti-inflammatory mechanism of macrophages following ADAR1 upregulation. A murine sepsis model was established by cecal ligation and puncture (CLP). Mice were randomly assigned to sham, CLP, and CLP+ADAR1 groups. Hematoxylin and eosin (HE) staining and fluorescence isothiocyanate-dextran were used to evaluate intestinal injury and permeability. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and Luminex assays were performed to detect changes in the expression of inflammatory cytokines. Adenoviruses were used to express ADAR1 in RAW 264.7 cells. Ribonucleoprotein immunoprecipitation analysis was conducted to detect the binding of ADAR1 and miRNAs. A dual-luciferase reporter assay was used to detect the binding of miRNAs and regulatory factors. We observed that ADAR1 significantly increased the expression of suppressor of cytokine signaling 3 (SOCS3) in macrophages and reduced the expression of interleukin-6 in macrophages and the serum, thereby reducing intestinal permeability and mucosal injury in mice with sepsis. The RNA-ribonucleoprotein immunoprecipitation binding assay and qRT-PCR demonstrated a direct interaction between ADAR1 and pri-miR-30a. The luciferase assay demonstrated that SOCS3 was significantly inhibited by miR-30a-5p, the mature product of miR-30a. Thus, ADAR1 exerts a protective effect against sepsis by reducing inflammation and organ damage via the ADAR1-miR-30a-SOCS3 axis.

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ADAR1: A New Target for Immuno-oncology Therapy

Abstract: Three recent studies by Ishizuka et al. (2019), Liu et al. (2019), and Gannon et al. (2018) show that deleting RNA editing enzyme ADAR1 could induce higher cell lethality and render tumor cells more vulnerable to immunotherapy, pinpointing ADAR1 as a new immuno-oncology target.

Cited by 58 publications

References 14 publications

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Widespread interaction between ADAR1 and transcriptional byproducts

ADAR1 Alleviates Inflammation in a Murine Sepsis Model via the ADAR1-miR-30a-SOCS3 Axis

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