A‐to‐I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy

Abstract

ADAR deaminases catalyze adenosine‐to‐inosine (A‐to‐I) editing on double‐stranded RNA (dsRNA) substrates that regulate an umbrella of biological processes. One of the two catalytically active ADAR enzymes, ADAR1, plays a major role in innate immune responses by suppression of RNA sensing pathways which are orchestrated through the ADAR1‐dsRNA‐MDA5 axis. Unedited immunogenic dsRNA substrates are potent ligands for the cellular sensor MDA5. Upon activation, MDA5 leads to the induction of interferons and expression of hundreds of interferon‐stimulated genes with potent antiviral activity. In this way, ADAR1 acts as a gatekeeper of the RNA sensing pathway by striking a fine balance between innate antiviral responses and prevention of autoimmunity. Reduced editing of immunogenic dsRNA by ADAR1 is strongly linked to the development of common autoimmune and inflammatory diseases. In viral infections, ADAR1 exhibits both antiviral and proviral effects. This is modulated by both editing‐dependent and editing‐independent functions, such as PKR antagonism. Several A‐to‐I RNA editing events have been identified in viruses, including in the insidious viral pathogen, SARS‐CoV‐2 which regulates viral fitness and infectivity, and could play a role in shaping viral evolution. Furthermore, ADAR1 is an attractive target for immuno‐oncology therapy. Overexpression of ADAR1 and increased dsRNA editing have been observed in several human cancers. Silencing ADAR1, especially in cancers that are refractory to immune checkpoint inhibitors, is a promising therapeutic strategy for cancer immunotherapy in conjunction with epigenetic therapy. The mechanistic understanding of dsRNA editing by ADAR1 and dsRNA sensing by MDA5 and PKR holds great potential for therapeutic applications.This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease

Dimerization of ADAR1 modulates site-specificity of RNA editing

“…Interestingly, our finding, that some but not all editing sites are affected when the dimerization surface of dsRBD3 is mutated suggests that dimerization is only required for efficient editing of some sites. Most importantly, this shows that dimerization has different impact on different sites, and as such, inhibition of dimerization, as opposed to inhibition of catalytic activity, might be an attractive way to pursue for modulating ADAR1 editing activity in the context of immunotherapy [26,59,60]. Towards this goal, deciphering the substrates affected by dsRBD3 dimerization will require more in-depth studies on how dimerization mutations affect transcriptome-wide editing.…”

Significant Variations in Double-Stranded RNA Levels in Cultured Skin Cells

“…Under physiological circumstances, transcription of the low complexity regions is minor with spurious dsRNA edited by ADAR1 p110 and contained in the nucleus. Increased transcription of repetitive elements in response to -for example-DNA de-methylation or a knockdown of ADAR1 leads to the export of dsRNA molecules into the cytoplasm [7].…”

Identification of prognostic RNA editing profiles for clear cell renal carcinoma

“…After in-depth research, scientists have identified hundreds of A-to-I RNA editing sites, which are specifically labeled as differential editing sites because they are closely associated with clinical outcomes of cancer ( 21 ). The study reveals significant differences in the editing of ubiquitination sites between tumor and non-tumor samples, as well as between different tumor subtypes in the TCGA dataset.…”