RNA-specific Adenosine Deaminase Research Articles

All-trans retinoic acid-mediated ADAR1 degradation synergizes with PD-1 blockade to suppress pancreatic cancer.

As a double-stranded RNA-editing enzyme and an interferon-stimulated gene, double-stranded RNA-specific adenosine deaminase (ADAR1) suppresses interferon signaling and contributes to immunotherapy resistance. Suppression of ADAR1 overcomes immunotherapy resistance in preclinical models, but has not yet been translated to clinical settings. By conducting a screening of a subset of the FDA-approved drugs, we found that all-trans retinoic acid (ATRA, also known as tretinoin) caused ADAR1 protein degradation through ubiquitin-proteasome pathways and concomitantly increased PD-L1 expression in pancreatic and breast cancers. In addition, the combination of ATRA and PD-1 blockade reprogrammed the tumor microenvironment and unleashed antitumor immunity and thereby impeded tumor growth in pancreatic cancer mouse models. In a pilot clinical trial, a higher dose of ATRA plus the anti-PD-1 antibody nivolumab prolonged median overall survival in patients with chemotherapy-resistant pancreatic cancer compared to a lower dose of the same regimen. In this study, ATRA was the first drug to be found to cause ADAR1 degradation. We propose translation of a promising 2-pronged antitumor strategy using ATRA and nivolumab to convert immunologically "cold" into "hot" tumors susceptible to immune checkpoint blockade.

Nuclear eNOS interacts with and S-nitrosates ADAR1 to modulate endothelial gene expression

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Collaborative Research Centre (CRC 1366); Chinese Scholarship Council (CSC) Introduction and Aim Nitric oxide (NO) generated by the endothelial NO synthase (eNOS) regulates vascular tone and endothelial homeostasis to counteract vascular inflammation. The effects of NO are attributable to its interaction with heme-containing proteins e.g., soluble guanylyl cyclase, or to the S-nitrosation of proteins. Most eNOS is localized to the cell membrane or the Golgi apparatus, however, it has also been detected in the nucleus. In this study, we assessed the role of nuclear eNOS in endothelial cells. Methods and Results Confocal microscopy studies confirmed the presence of eNOS in the nucleus of unstimulated human and murine endothelial cells (ex vivo and in vitro) and stimulation with vascular endothelial growth factor (VEGF) increased eNOS nuclear translocation. Co-immunoprecipitation studies coupled with proteomics revealed the VEGF-dependent association of nuclear eNOS with 81 proteins involved in RNA binding and processing. Among these, nuclear eNOS bound double-stranded RNA-specific adenosine deaminase 1 (ADAR1), an enzyme involved in RNA editing via the deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA). ADAR1 was S-nitrosated in human endothelial cells and the knockdown of eNOS was associated with an increase in dsRNA (immunofluorescence) and altered ADAR1-mediated A-I editing (RNA seq). The accumulation of dsRNA in human endothelial cells lacking eNOS led to the activation of the interferon α/β signalling pathway (e.g., MX2, OASL, OAS1/2/3, RNASEL) and the downregulation of cell cycle-related genes. As a result, growth factor-stimulated cell proliferation was abrogated and basal as well as tumour necrosis factor- or H2O2-induced cell death were increased. Furthermore, the increased dsRNA in endothelial cells lacking eNOS elicited the activation of interferon-induced, dsRNA-activated protein kinase, which in turn phosphorylated the eukaryotic translation initiation factor 2A. Accordingly, new protein synthesis was inhibited following eNOS knockdown (immunofluorescence and mass spectrometry). Conclusion These results demonstrated that eNOS/NO signalling regulates endothelial type I interferon signalling and affects translation, cell cycle and cell death through S-nitrosation of ADAR1.

Serotonin 2C receptor in a rat model of temporal lobe epilepsy: From brainstem expression to pharmacological blockade in relation to ventilatory function.

Because of its involvement in breathing control and neuronal excitability, dysregulation of the serotonin (5-HT) 2C receptor (5-HT2C) might play a key role in sudden unexpected death in epilepsy. Seizure-induced respiratory arrest is thus prevented by a 5-HT2B/C agonist in different seizure model. However, the specific contribution of 5-HT2C in chronic epilepsy-related respiratory dysfunction remains unknown. In a rat model of temporal lobe epilepsy (EPI rats), in which we previously reported interictal respiratory dysfunctions and a reduction of brainstem 5-HT tone, quantitative reverse transcriptase polymerase chain reaction showed overexpression of TPH2 (5-HT synthesis enzyme), SERT (5-HT reuptake transporter), and 5-HT2C transcript levels in the brainstem of EPI rats, and of RNA-specific adenosine deaminase (ADAR1, ADAR2) involved in the production of 5-HT2C isoforms. Interictal ventilation was assessed with whole-body plethysmography before and 2 h after administration of SB242084 (2 mg/kg), a specific antagonist of 5-HT2C. As expected, SB242084 administration induced a progressive decrease in ventilatory parameters and an alteration of breathing stability in both control and EPI rats. However, the size of the SB242084 effect was lower in EPI rats than in controls. Increased 5-HT2C gene expression in the brainstem of EPI rats could be part of a compensatory mechanism against epilepsy-related low 5-HT tone and expression of 5-HT2C isoforms for which 5-HT affinity might be lower.

An adenine base editor variant expands context compatibility.

Adenine base editors (ABEs) are precise gene-editing agents that convert A:T pairs into G:C through a deoxyinosine intermediate. Existing ABEs function most effectively when the target A is in a TA context. Here we evolve the Escherichia coli transfer RNA-specific adenosine deaminase (TadA) to generate TadA8r, which extends potent deoxyadenosine deamination to RA (R = A or G) and is faster in processing GA than TadA8.20 and TadA8e, the two most active TadA variants reported so far. ABE8r, comprising TadA8r and a Streptococcus pyogenes Cas9 nickase, expands the editing window at the protospacer adjacent motif-distal end and outperforms ABE7.10, ABE8.20 and ABE8e in correcting disease-associated G:C-to-A:T transitions in the human genome, with a controlled off-target profile. We show ABE8r-mediated editing of clinically relevant sites that are poorly accessed by existing editors, including sites in PCSK9, whose disruption reduces low-density lipoprotein cholesterol, and ABCA4-p.Gly1961Glu, the most frequent mutation in Stargardt disease.

Covalent drug collaboration formed

Covant has entered a collaboration with Boehringer Ingelheim to develop small-molecule covalent drugs for immuno-oncology. The companies aim to inhibit an RNA-specific adenosine deaminase enzyme to improve the immune system’s response to tumors by turning “cold” tumors into “hot” tumors. The developers plan for their inhibitor to be combined with other immunotherapies. Boehringer Ingelheim will pay Covant $10 million up front for the discovery of covalent candidates and $471 million in potential milestones, plus royalties.

Abstract A019: Epigenetic regulation by H3K9 methylation enables resistance to anti-androgen therapy in prostate cancer

Abstract Prostate cancer (PCa) is a major cause of cancer mortality in the United States. Androgen receptor (AR) is the key transcriptional regulator for the development and progression of prostate cancer. Androgen deprivation therapy (ADT) with medical castration and treatment with second-generation anti-androgens such as enzalutamide and abiraterone acetate are important treatments for advanced prostate cancer. Previous studies have shown resistance to enzalutamide develops through various alternative molecular mechanisms including AR gene amplification, mutations in the ligand binding domains of AR, and increased expression of glucocorticoid receptor (GR). Recent reports further indicate that resistance to enzalutamide is accompanied with various de novo genomic and transcriptional changes that lead to reduced AR activity and acquisition of stem-cell like properties along with increased expression of genes associated with epithelial-to-mesenchymal transition and inflammatory signaling pathway, including interleukin 6 (IL6), janus kinase-signal transducer and activator of transcription (JAK-STAT) and interferon (IFN). In our study, we have unraveled a novel mechanism of epigenetic regulation mediated by H3K9 methylation in response to anti-androgen treatment in PCa cells. We have shown enzalutamide treatment leads to aberrant activation of endogenous retroelements (REs) which causes accumulation of double stranded RNA (dsRNA) in the PCa cells. This results in an antiviral response mediated via IFN signaling and induction of apoptosis, a phenomenon known as viral mimicry. Using a forward genetic screen, we have identified that the epigenetic machinery associated with H3K9 methylation is responsible for suppressing the aberrant transcription of REs in response to anti-androgen treatment. Further, overexpression of the terminal H3K9me3 writers lead to the suppression of REs whereas pharmacological or genetic inhibition of H3K9 trimethylation writers and readers restored REs expression, abrogating resistance to anti-androgen. Moreover, elevated expression of terminal H3K9me3 writers is associated with poor outcomes in patients subjected to hormonal therapy. Interestingly, we have observed that inhibition of double-stranded RNA-specific adenosine deaminase (ADAR1) leads to accumulation of dsRNA and modulates GR expression in PCa cells. Taken together, our study highlights the role of H3K9 trimethylation in mediating resistance to anti-androgen therapy in prostate cancer. Notably, members of the H3K9 trimethylation machinery could potentially serve as therapeutic targets and combinatorial approaches targeting epigenetic regulatory enzymes as well as androgen signaling axis could be a promising strategy for overcoming drug resistance and immune evasion in prostate cancer. Citation Format: Ritika Tiwari, Mehdi Baratchian, Michael Berk, Jianneng Li, Amy Guerinot, Vladimir Makarov, Timothy A. Chan, Abhishek A. Chakraborty, Nima Sharifi. Epigenetic regulation by H3K9 methylation enables resistance to anti-androgen therapy in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A019.

Regulation of miRNA content. Part 1. Editing miRNA. Тailing miRNA

This scientific review presents the processes of regulation of miRNA content. To write the article, information was searched using Scopus, Web of Science, MedLine, PubMed, Google Scholar, EMBASE, Global Health, The Cochrane Library, CyberLeninka databases. The article presents the characteristics of the processes of microRNA editing and microRNA tailing, which regulate the content of microRNA through the transcription control. It is emphasized that editing is the most important mechanism of posttranscriptional regulation of microRNA that occurs with the help of RNA-specific adenosine deaminase. The article shows that editing leads to a change in the secondary structure of the microRNA molecule and the deviation of the process of microRNA maturation. It is shown that microRNA tailing is a posttranscriptional elongation of the tail of the molecule by adding nucleotides to the 3’-end of RNA. It has been found that uridinylation is a very common posttranscriptional process that regulates gene expression. The effect of uridinylation on microRNA biogenesis has been demonstrated on the example of the miR let-7 family, which inhibits proliferation and promotes cell differentiation. It has been established that another type of microRNA tailing, namely adenylation, most often contributes to the stabilization of the molecule, but in some cases can lead to microRNA degradation. Thus, the regulation of miRNA content is carried out by editing miRNA, microRNA tailing. Due to editing, the secondary structure of the microRNA molecule changes and the microRNA maturation process deviates. MicroRNA tailing is a post-transcriptional elongation of the tail of the molecule by adding nucleotides to the 3’-end of RNA by polyuridinylation or polyadenylation. Uridinylation affects the processing and degradation of miRNA precursors with different molecular effects, which in some cases contribute to the development of diseases.

Conservation of A-to-I RNA editing in bowhead whale and pig.

RNA editing is a post-transcriptional process in which nucleotide changes are introduced into an RNA sequence, many of which can contribute to proteomic sequence variation. The most common type of RNA editing, contributing to nearly 99% of all editing events in RNA, is A-to-I (adenosine-to-inosine) editing mediated by double-stranded RNA-specific adenosine deaminase (ADAR) enzymes. A-to-I editing at ‘recoding’ sites results in non-synonymous substitutions in protein-coding sequences. Here, we present studies of the conservation of A-to-I editing in selected mRNAs between pigs, bowhead whales, humans and two shark species. All examined mRNAs–NEIL1, COG3, GRIA2, FLNA, FLNB, IGFBP7, AZIN1, BLCAP, GLI1, SON, HTR2C and ADAR2 –showed conservation of A-to-I editing of recoding sites. In addition, novel editing sites were identified in NEIL1 and GLI1 in bowhead whales. The A-to-I editing site of human NEIL1 in position 242 was conserved in the bowhead and porcine homologues. A novel editing site was discovered in Tyr244. Differential editing was detected at the two adenosines in the NEIL1 242 codon in both pig and bowhead NEIL1 mRNAs in various tissues and organs. No conservation of editing of KCNB1 and EEF1A mRNAs was seen in bowhead whales. In silico analyses revealed conservation of five adenosines in ADAR2, some of which are subject to A-to-I editing in bowheads and pigs, and conservation of a regulatory sequence in GRIA2 mRNA that is responsible for recognition of the ADAR editing enzyme.

Proteome Diversification by RNA Editing.

RNA editing is an RNA modification that alters the RNA sequence relative to its genomic blueprint. The most common type of RNA editing is A-to-I editing by double-stranded RNA-specific adenosine deaminase (ADAR) enzymes. Editing of a protein-coding region within the RNA molecule may result in non-synonymous substitutions, leading to a modified protein product. These editing sites, also known as "recoding" sites, contribute to the complexity and diversification of the proteome. Recent computational transcriptomic studies have identified thousands of recoding sitesin multiple species, many of which are conserved within (but not usually across) lineages and have functional and evolutionary importance. In this chapter we describe the recoding phenomenon across species, consider its potential utility for diversity and adaptation, and discuss its evolution.

ADAR1-Dependent RNA Editing Promotes MET and iPSC Reprogramming by Alleviating ER Stress.

RNA editing of adenosine to inosine (A to I) is catalyzed by ADAR1 and dramatically alters the cellular transcriptome, although its functional roles in somatic cell reprogramming are largely unexplored. Here, we show that loss of ADAR1-mediated A-to-I editing disrupts mesenchymal-to-epithelial transition (MET) during induced pluripotent stem cell (iPSC) reprogramming and impedes acquisition of induced pluripotency. Using chemical and genetic approaches, we show that absence of ADAR1-dependent RNA editinginducesaberrant innate immune responses through the double-stranded RNA (dsRNA) sensor MDA5, unleashing endoplasmic reticulum (ER) stress and hindering epithelial fate acquisition. We found that A-to-I editing impedes MDA5 sensing and sequestration of dsRNAs encoding membrane proteins, which promote ER homeostasis by activating the PERK-dependent unfolded protein response pathway to consequently facilitate MET. This study therefore establishes a critical role for ADAR1 and its A-to-I editing activity duringcell fate transitions and delineates a key regulatory layer underlying MET to control efficient reprogramming.

ADAR1 Transcriptome editing promotes breast cancer progression through the regulation of cell cycle and DNA damage response

RNA editing has emerged as a novel mechanism in cancer progression. The double stranded RNA-specific adenosine deaminase (ADAR) modifies the expression of an important proportion of genes involved in cell cycle control, DNA damage response (DDR) and transcriptional processing, suggesting an important role of ADAR in transcriptome regulation. Despite the phenotypic implications of ADAR deregulation in several cancer models, the role of ADAR on DDR and proliferation in breast cancer has not been fully addressed. Here, we show that ADAR expression correlates significantly with clinical outcomes and DDR, cell cycle and proliferation mRNAs of previously reported edited transcripts in breast cancer patients. ADAR's knock-down in a breast cancer cell line produces stability changes of mRNAs involved in DDR and DNA replication. Breast cancer cells with reduced levels of ADAR show a decreased viability and an increase in apoptosis, displaying a significant decrease of their DDR activation, compared to control cells. These results suggest that ADAR plays an important role in breast cancer progression through the regulation of mRNA stability and expression of those genes involved in proliferation and DDR impacting the viability of breast cancer cells.

Integrated analysis of mRNA-miRNA expression in Tilapia infected with Tilapia lake virus (TiLV) and identifies primarily immuneresponse genes

We investigated differential gene expression in Tilapia infected with the Tilapia Lake virus (TiLV).We used high-throughput sequencing to identify mRNAs and miRNAs involved in TiLV infection progression We identified 25,359 differentially expressed genes that included 863 new genes. We identified 1770, 4142 and 4947 differently expressed genes comparing non-infected controls with 24 and 120 h infections and between the infected groups, respectively. These genes were enriched to 291 GO terms and 62 KEGG pathways and included immune system progress and virion genes. High-throughput miRNA sequencing identified 316 conserved miRNAs, 525 known miRNAs and 592 novel miRNAs. Furthermore, 138, 198 and 153 differently expressed miRNAs were found between the 3 groups listed above, respectively. Target prediction revealed numerous genes including erythropoietin isoform X2, double-stranded RNA-specific adenosine deaminase isoform X1, bone morphogenetic protein 4 and tapasin-related protein that are involved in immune responsiveness. Moreover, these target genes overlapped with differentially expressed mRNAs obtained from RNA-seq. These target genes were significantly enriched to GO terms and KEGG pathways including immune system progress, virion and Wnt signaling pathways. Expression patterns of differentially expressed mRNA and miRNAs were validated in 20 mRNA and 19 miRNAs by qRT-PCR. We also were able to construct a miRNA-mRNA target network that can further understand the molecular mechanisms on the pathogenesis of TiLV and guide future research in developing effective agents and strategies to combat TiLV infections in Tilapia.

Ethanol Preference and Drinking Behavior Are Controlled by RNA Editing in the Nucleus Accumbens.

RNA editing plays critical roles in normal brain function, and alteration of its activity causes various disorders. We previously found that chronic consumption of ethanol was associated with increased levels of RNA editing of serotonin 2C receptor in the nucleus accumbens (NAc). However, it remains unknown whether RNA editing in the NAc modulates alcohol addiction through the brain reward system. To investigate the involvement of NAc RNA editing in alcohol addiction, we generated NAc-specific knockout mice of the double-stranded RNA-specific adenosine deaminase ADAR2 using AAV-GFP/Cre and conducted a battery of behavioral tests including anxiety- and depression-like behaviors. In addition, NAc-specific ADAR2 knockout mice were exposed to ethanol vapor for 20 days, followed by ethanol-drinking and conditioned place preference (CPP) tests. NAc-specific ADAR2 knockout mice showed a significant decrease in locomotor activity in the open field test although they did not develop anxiety- and depression-like behaviors. In addition, the enhancements of ethanol intake and ethanol preference that are usually observed after chronic ethanol vapor exposure were significantly reduced in these mice. These results suggest that ADAR2-mediated RNA editing in the NAc is involved in determination of alcohol preference after chronic alcohol consumption.

The Roles of NLRP3 Inflammasome and ADAR1 in Diabetic Foot Ulcer

Infected diabetic foot ulcer (DFU) is an important problem because it is a limb or even life threatening, and burdens a great financial load to the community. It’s shown that circulating inflammatory proteins are reputed to be of poor value for diagnosing DFU as lack of specificity. Therefore it's necessary to investigate newer discussed inflammatory parameters. NLRP3 inflammasome, a multiprotein complex consists of NLRP3, ASC and pro-caspase-1 and controls the production of IL-1β and IL-18, is an important contributor to the development of type 2 diabetes. The RNA-specific adenosine deaminase (ADAR1) is interferon-inducible double stranded (ds) RNA-binding protein, which is demonstrated to inhibit the production of type I interferons and various proinflammatory cytokines such as TNF-a and IL-6. But little is known about the ex vivo profile of NLRP3 inflammasome and ADAR1 in DFU. On this basis the aim of our study was to evaluate the role of NLRP3 inflammasome and ADAR1 in subjects with DFU in comparison with subjects without DFU. We completed a study including 20 healthy volunteers, 20 newly diagnosed type 2 diabetic (T2D) patients and 30 DFU patients (wagner2-4). Then peripheral blood mononuclear cells were collected from all subjects and NLRP3, ASC, Caspase-1, ADAR1 contents were detected by real-time PCR. The results showed that mRNA of NLRP3, ASC, Caspase-1 in T2D patients were significantly higher than those of healthy persons, while 2-fold lower than DFU patients (both P < 0.05); ADAR1 mRNA in T2D patients were significantly higher than those of healthy persons (P < 0.05). Interestingly, however, ADAR1 mRNA in DFU patients were decreased by 3-fold compared with T2D (P < 0.05), indicating that ADAR1 is increased in low-grade inflammation state but decreased in severe infectious state. This study suggests that NLRP3 inflammasome and ADAR1 may be useful markers to diagnose and follow the DFU. Further investigation is needed and it will be interesting to investigate the connection between them. Disclosure F. Wang: None. L. Zhao: None. W. Yang: None. H. He: None. Z. Mo: None.

Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis

Alterations in microRNA (miRNA) processing have been previously linked to aging. Here we used the small molecule enoxacin to pharmacologically interfere with miRNA biogenesis and study how it affects aging in C. elegans. Enoxacin extended worm lifespan and promoted survival under normal and oxidative stress conditions. Enoxacin-induced longevity required the transcription factor SKN-1/Nrf2 and was blunted by the antioxidant N-acetyl-cysteine, suggesting a prooxidant-mediated mitohormetic response. The longevity effects of enoxacin were also dependent on the miRNA pathway, consistent with changes in miRNA expression elicited by the drug. Among these differentially expressed miRNAs, the widely conserved miR-34-5p was found to play an important role in enoxacin-mediated longevity. Enoxacin treatment down-regulated miR-34-5p and did not further extend lifespan of long-lived mir-34 mutants. Moreover, N-acetyl-cysteine abrogated mir-34(gk437)-induced longevity. Evidence also points to double-stranded RNA-specific adenosine deaminases (ADARs) as new targets of enoxacin since ADAR loss-of-function abrogates enoxacin-induced lifespan extension. Thus, enoxacin increases lifespan by reducing miR-34-5p levels, interfering with the redox balance and promoting healthspan.

ADAR Mediated RNA Editing Modulates MicroRNA Targeting in Human Breast Cancer.

RNA editing by RNA specific adenosine deaminase acting on RNA (ADAR) is increasingly being found to alter microRNA (miRNA) regulation. Editing of miRNA transcripts can affect their processing, as well as which messenger RNAs (mRNAs) they target. Further, editing of target mRNAs can also affect their complementarity to miRNAs. Notably, ADAR editing is often increased in malignancy with the effect of these RNA changes being largely unclear. In addition, numerous reports have now identified an array of miRNAs that directly contribute to various malignancies although the majority of their targets remain largely undefined. Here we propose that modulating the targets of miRNAs via mRNA editing is a frequent occurrence in cancer and an underappreciated participant in pathology. In order to more accurately characterize the relationship between these two regulatory processes, this study examined RNA editing events within mRNA sequences of two breast cancer cell lines (MCF-7 and MDA-MB-231) and determined whether or not these edits could modulate miRNA associations. Computational analyses of RNA-Seq data from these two cell lines identified over 50,000 recurrent editing sites within human mRNAs, and many of these were located in 3’ untranslated regions (UTRs). When these locations were screened against the list of currently-annotated miRNAs we discovered that editing caused a subset (~9%) to have significant alterations to mRNA complementarity. One miRNA in particular, miR-140–3p, is known to be misexpressed in many breast cancers, and we found that mRNA editing allowed this miRNA to directly target the apoptosis inducing gene DFFA in MCF-7, but not in MDA-MB-231 cells. As these two cell lines are known to have distinct characteristics in terms of morphology, invasiveness and physiological responses, we hypothesized that the differential RNA editing of DFFA in these two cell lines could contribute to their phenotypic differences. Indeed, we confirmed through western blotting that inhibiting miR-140–3p increases expression of the DFFA protein product in MCF-7, but not MDA-MB-231, and further that inhibition of miR-140–3p also increases cellular growth in MCF-7, but not MDA-MB-231. Broadly, these results suggest that the creation of miRNA targets may be an underappreciated function of ADAR and may help further elucidate the role of RNA editing in tumor pathogenicity.

A-to-I RNA editing - immune protector and transcriptome diversifier.

Modifications of RNA affect its function and stability. RNA editing is unique among these modifications because it not only alters the cellular fate of RNA molecules but also alters their sequence relative to the genome. The most common type of RNA editing is A-to-I editing by double-stranded RNA-specific adenosine deaminase (ADAR) enzymes. Recent transcriptomic studies have identified a number of 'recoding' sites at which A-to-I editing results in non-synonymous substitutions in protein-coding sequences. Many of these recoding sites are conserved within (but not usually across) lineages, are under positive selection and have functional and evolutionary importance. However, systematic mapping of the editome across the animal kingdom has revealed that most A-to-I editing sites are located within mobile elements in non-coding parts of the genome. Editing of these non-coding sites is thought to have a critical role in protecting against activation of innate immunity by self-transcripts. Both recoding and non-coding events have implications for genome evolution and, when deregulated, may lead to disease. Finally, ADARs are now being adapted for RNA engineering purposes.

A novel mutation of the RNA-specific adenosine deaminase 1 gene in a Taiwanese patient with dyschromatosis symmetrica hereditaria and Becker's nevus-like lesion

A novel mutation of the RNA-specific adenosine deaminase 1 gene in a Taiwanese patient with dyschromatosis symmetrica hereditaria and Becker's nevus-like lesion

ADAR-mediated messenger RNA editing: analysis at the proteome level

Post-transcriptional RNA editing by RNA specific adenosine deaminases (ADAR) was discovered more than two decades ago. It provides additional regulation of animal and human transcriptome. In most cases, it occurs in nervous tissue, where, as a result of the reaction, adenosine is converted to inosine in particular sites of RNA. In case of messenger RNA, during translation, inosine is recognized as guanine leading to amino acid substitutions. Those substitutions are shown to affect substantially the function of proteins, e.g. subunits of the glutamate receptor. Nevertheless, most of the works on RNA editing use analysis of nucleic acids, even those which deal with a coding RNA. In this review, we propose the use of shotgun proteomics based on high resolution liquid chromatography and mass spectrometry for investigation of the effects of RNA editing at the protein level. Recently developed methods of big data processing allow combining the results of various omics techniques, being referred to as proteogenomics. The proposed proteogenomic approach for the analysis of RNA editing at the protein level will directly conduct a qualitative and quantitative analysis of protein edited sequences in the scale of whole proteome.

Double-stranded RNA-specific adenosine deaminase 1 (ADAR1) promotes EIAV replication and infectivity

Adenosine deaminases that act on RNA (ADARs) have been reported to be functional on various viruses. ADAR1 may exhibit antiviral or proviral activity depending on the type of virus. Human immunodeficiency virus (HIV)-1 is the most well-studied lentivirus with respect to its interaction with ADAR1, and variable results have been reported. In this study, we demonstrated that equine ADAR1 (eADAR1) was a positive regulator of equine infectious anemia virus (EIAV), another lentivirus of the Retroviridae family. First, eADAR1 significantly promoted EIAV replication, and the enhancement of viral protein expression was associated with the long terminal repeat (LTR) and Rev response element (RRE) regions. Second, the RNA binding domain 1 of eADAR1 was essential only for enhancing LTR-mediated gene expression. Third, in contrast with APOBEC proteins, which have been shown to reduce lentiviral infectivity, eADAR1 increased the EIAV infectivity. This study indicated that eADAR1 was proviral rather than antiviral for EIAV.