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Adenosine to inosine (A-to-I) RNA editing, the most prevalent type of RNA editing in metazoans, is carried out by adenosine deaminases (ADARs) in double-stranded RNA regions. Several computational approaches have been recently developed to identify A-to-I RNA editing sites from sequencing data, each addressing a particular issue. Here, we present RNA Editing Sites Identification and Classification (RESIC), an efficient pipeline that combines several approaches for the detection and classification of RNA editing sites. The pipeline can be used for all organisms and can use any number of RNA-sequencing datasets as input. RESIC provides (1) the detection of editing sites in both repetitive and non-repetitive genomic regions; (2) the identification of hyper-edited regions; and (3) optional exclusion of polymorphism sites to increase reliability, based on DNA, and ADAR-mutant RNA sequencing datasets, or SNP databases. We demonstrate the utility of RESIC by applying it to human, successfully overlapping and extending the list of known putative editing sites. We further tested changes in the patterns of A-to-I RNA editing, and RNA abundance of ADAR enzymes, following SARS-CoV-2 infection in human cell lines. Our results suggest that upon SARS-CoV-2 infection, compared to mock, the number of hyper editing sites is increased, and in agreement, the activity of ADAR1, which catalyzes hyper-editing, is enhanced. These results imply the involvement of A-to-I RNA editing in conceiving the unpredicted phenotype of COVID-19 disease. RESIC code is open-source and is easily extendable. [ABSTRACT FROM AUTHOR]

Adenosine-to-inosine RNA editing is a conserved process, which is performed by ADAR enzymes. By changing nucleotides in coding regions of genes and altering codons, ADARs expand the cell's protein repertoire. This function of the ADAR enzymes is essential for human brain development. However, most of the known editing sites are in non-coding repetitive regions in the transcriptome and the purpose of editing in these regions is unclear. Recent studies, which have shown that editing levels of transcripts vary between tissues and developmental stages in many organisms, suggest that the targeted RNA and ADAR editing are both regulated. We discuss the implications of these findings, and the possible role of RNA editing in innate immunity. [ABSTRACT FROM PUBLISHER]

In recent years, A-to-I RNA modifications performed by the Adenosine Deaminase Acting on RNA (ADAR) protein family were found to be expressed at altered levels in multiple human malignancies. A-to-I RNA editing changes adenosine to inosine on double stranded RNA, thereby changing transcript sequence and structure. Although A-to-I RNA editing have the potential to change essential mRNA transcripts, affecting their corresponding protein structures, most of the human editing sites identified to date reside in non-coding repetitive transcripts such as Alu elements. Therefore, the impact of the hypo- or hyper-editing found in specific cancers remains unknown. Moreover, it is yet unclear whether or not changes in RNA editing and ADAR expression levels facilitate or even drive cancer progression or are just a byproduct of other affected pathways. In both cases, however, the levels of RNA editing and ADAR enzymes can possibly be used as specific biomarkers, as their levels change differently in specific malignancies. More significantly, recent studies suggest that ADAR enzymes can be used to reverse the oncogenic process, suggesting a potential for gene therapies. This review focuses on new findings that suggest that RNA editing by ADARs can affect cancer progression and even formation. We also discuss new possibilities of using ADAR enzymes and RNA editing as cancer biomarkers, indicators of chemotherapeutic drug sensitivity, and even to be themselves potential therapeutic tools. [ABSTRACT FROM AUTHOR]

A-to-I RNA editing, catalyzed by ADAR proteins, is widespread in eukaryotic transcriptomes. Studies showed that, in C. elegans , ADR-2 can actively deaminate dsRNA, whereas ADR-1 cannot. Therefore, we set out to study the effect of each of the ADAR genes on the RNA editing process. We performed comprehensive phenotypic, transcriptomics, proteomics, and RNA binding screens on worms mutated in a single ADAR gene. We found that ADR-1 mutants exhibit more-severe phenotypes than ADR-2, and some of them are a result of non-editing functions of ADR-1. We also show that ADR-1 significantly binds edited genes and regulates mRNA expression, whereas the effect on protein levels is minor. In addition, ADR-1 primarily promotes editing by ADR-2 at the L4 stage of development. Our results suggest that ADR-1 has a significant role in the RNA editing process and in altering editing levels that affect RNA expression; loss of ADR-1 results in severe phenotypes. • Changes in RNA editing levels are harmful to normal development • In C. elegans , editing affects genes at the RNA level, but not at the protein level • ADR-1 function is to promote editing by ADR-2 at the L4 larval stage • C. elegans ADR-1 has developmental functions that are unrelated to RNA editing Ganem et al. report that the C. elegans enzymatic-inactive ADR-1 regulates A-to-I RNA editing by directing editing by ADR-2, mainly at the L4 developmental stage. Changes in RNA editing levels severely affect normal development by changing RNA levels, but not protein levels. [ABSTRACT FROM AUTHOR]

Adenosine to inosine (A-to-I) RNA editing is a highly conserved regulatory process carried out by adenosine-deaminases (ADARs) on double-stranded RNA (dsRNAs). Although a considerable fraction of the transcriptome is edited, the function of most editing sites is unknown. Previous studies indicate changes in A-to-I RNA editing frequencies following exposure to several stress types. However, the overall effect of stress on the expression of ADAR targets is not fully understood. Here, we performed high-throughput RNA sequencing of wild-type and ADAR mutant Caenorhabditis elegans worms after heat-shock to analyze the effect of heat-shock stress on the expression pattern of genes. We found that ADAR regulation following heat-shock does not directly involve heat-shock related genes. Our analysis also revealed that long non-coding RNAs (lncRNAs) and pseudogenes, which have a tendency for secondary RNA structures, are enriched among upregulated genes following heat-shock in ADAR mutant worms. The same group of genes is downregulated in ADAR mutant worms under permissive conditions, which is likely, considering that A-to-I editing protects endogenous dsRNA from RNA-interference (RNAi). Therefore, temperature increases may destabilize dsRNA structures and protect them from RNAi degradation, despite the lack of ADAR function. These findings shed new light on the dynamics of gene expression under heat-shock in relation to ADAR function. [ABSTRACT FROM AUTHOR]