<scp>RNA</scp>‐editing enzymes <scp>ADAR</scp>1 and <scp>ADAR</scp>2 coordinately regulate the editing and expression of <i>Ctn <scp>RNA</scp></i>

Anantharaman, Aparna; Gholamalamdari, Omid; Khan, Abid; Yoon, Je‐Hyun; Jantsch, Michael F.; Hartner, Jochen C.; Gorospe, Myriam; Prasanth, Supriya G.; Prasanth, Kannanganattu V.

doi:10.1002/1873-3468.12795

Cited by 22 publications

(16 citation statements)

References 83 publications

(137 reference statements)

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“…Given that HuR stabilizes RNAs to regulate gene expression [59][60][61], it is tempting to speculate that RNA editing sites promote the binding of HuR to stabilize the edited transcripts, as we have shown in our previous study for cathepsin S (CTSS) in endothelial cells [19]. Although an earlier study indicated such a mechanism of action [58], two other studies that investigated this interaction between RNA editing and HuR suggest the opposite [62,63]. These studies report that HuR, as a de-stabilizing enzyme influenced by the presence of RNA editing sites in the target RNA, nuclear-retained Cat2-transcribed nuclear RNA (Ctn RNA) [62,63].…”

Section: Discussionmentioning

confidence: 86%

“…Although an earlier study indicated such a mechanism of action [58], two other studies that investigated this interaction between RNA editing and HuR suggest the opposite [62,63]. These studies report that HuR, as a de-stabilizing enzyme influenced by the presence of RNA editing sites in the target RNA, nuclear-retained Cat2-transcribed nuclear RNA (Ctn RNA) [62,63]. As we did not investigate the stability of RNA in this study, we lack the evidence to refute these previous two studies.…”

Section: Discussionmentioning

confidence: 96%

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Investigation of RNA Editing Sites within Bound Regions of RNA-Binding Proteins

et al. 2019

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Studies in epitranscriptomics indicate that RNA is modified by a variety of enzymes. Among these RNA modifications, adenosine to inosine (A-to-I) RNA editing occurs frequently in the mammalian transcriptome. These RNA editing sites can be detected directly from RNA sequencing (RNA-seq) data by examining nucleotide changes from adenosine (A) to guanine (G), which substitutes for inosine (I). However, a careful investigation of such nucleotide changes must be conducted to distinguish sequencing errors and genomic mutations from the genuine editing sites. Building upon our recent introduction of an easy-to-use bioinformatics tool, RNA Editor, to detect RNA editing events from RNA-seq data, we examined the extent by which RNA editing events affect the binding of RNA-binding proteins (RBP). Through employing bioinformatic techniques, we uncovered that RNA editing sites occur frequently in RBP-bound regions. Moreover, the presence of RNA editing sites are more frequent when RNA editing islands were examined, which are regions in which RNA editing sites are present in clusters. When the binding of one RBP, human antigen R [HuR; encoded by ELAV-like protein 1 (ELAV1)], was quantified experimentally, its binding was reduced upon silencing of the RNA editing enzyme adenosine deaminases acting on RNA (ADAR) compared to the control—suggesting that the presence of RNA editing islands influence HuR binding to its target regions. These data indicate RNA editing as an important mediator of RBP–RNA interactions—a mechanism which likely constitutes an additional mode of post-transcription gene regulation in biological systems.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 96%

Investigation of RNA Editing Sites within Bound Regions of RNA-Binding Proteins

et al. 2019

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“…In addition, binding sites for HuR are present in close proximity to ADAR1 binding sites, and both enzymes appear to directly or indirectly interact to regulate transcript stability [88,89]. For example, ADAR1 and ADAR2 prevent destabilization of the Cat2 transcribed nuclear RNA (CTN) transcript, which is mediated by HuR in complex with poly(A)-specific ribonuclease deadenylase (PARN), by competing for specific binding sites within the target transcript [90,91].…”

Section: Regulation Of the Mirna Editing Machinery By Rna-binding Promentioning

confidence: 99%

Deciphering miRNAs’ Action through miRNA Editing

Sousa

Gjorgjieva

Dolicka

et al. 2019

IJMS

606

343

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MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or by promoting mRNA degradation. The outcome of a myriad of physiological processes and pathologies, including cancer, cardiovascular and metabolic diseases, relies highly on miRNAs. However, deciphering the precise roles of specific miRNAs in these pathophysiological contexts is challenging due to the high levels of complexity of their actions. Indeed, regulation of mRNA expression by miRNAs is frequently cell/organ specific; highly dependent on the stress and metabolic status of the organism; and often poorly correlated with miRNA expression levels. Such biological features of miRNAs suggest that various regulatory mechanisms control not only their expression, but also their activity and/or bioavailability. Several mechanisms have been described to modulate miRNA action, including genetic polymorphisms, methylation of miRNA promoters, asymmetric miRNA strand selection, interactions with RNA-binding proteins (RBPs) or other coding/non-coding RNAs. Moreover, nucleotide modifications (A-to-I or C-to-U) within the miRNA sequences at different stages of their maturation are also critical for their functionality. This regulatory mechanism called "RNA editing" involves specific enzymes of the adenosine/cytidine deaminase family, which trigger single nucleotide changes in primary miRNAs. These nucleotide modifications greatly influence a miRNA's stability, maturation and activity by changing its specificity towards target mRNAs. Understanding how editing events impact miRNA's ability to regulate stress responses in cells and organs, or the development of specific pathologies, e.g., metabolic diseases or cancer, should not only deepen our knowledge of molecular mechanisms underlying complex diseases, but can also facilitate the design of new therapeutic approaches based on miRNA targeting. Herein, we will discuss the current knowledge on miRNA editing and how this mechanism regulates miRNA biogenesis and activity.

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“…ADAR1 caries out the enzymatic reaction of deaminating adenosine to inosine within cellular dsRNA, in a process known as A-to-I editing. Induction of ADAR1 expression is prevalent in breast cancer(Fumagalli et al, 2015, Han et al, 2015, Paz-Yaacov et al, 2015, Peng et al, 2018, Anantharaman et al, 2017) and ADAR1-mediated A-to-I editing has been found to influence the levels of its targets in breast cancer(Gumireddy et al, 2016, Binothman et al, 2017, Dave et al, 2017, Nakano et al, 2017). Recent studies indicate that ADAR1 is over-represented in TNBC and may be correlated with poor prognosis when RNA editing is increased(Song et al, 2017, Sagredo et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

ADAR1 editing dependency in triple-negative breast cancer

Kung

Cottrell

Ryu

et al. 2020

Preprint

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14Triple-negative breast cancer (TNBC) is the deadliest form of breast cancer. Unlike other 15 types of breast cancer that can be effectively treated by targeted therapies, no such targeted 16 therapy exists for all TNBC patients. The ADAR1 enzyme carries out A-to-I editing of RNA to 17 prevent sensing of cellular double-stranded RNAs (dsRNA). ADAR1 is highly expressed in 18 breast cancer including TNBC. Here, we demonstrate that ADAR1 expression and editing 19 activity is required in TNBC cell lines but not in ER+ and/or Her2+ cells. In TNBC cells, 20 knockdown of ADAR1 attenuates proliferation and tumorigenesis. PKR expression is elevated in 21 TNBC and its activity is induced upon ADAR1-knockdown, which correlates with a decrease in 22 translation. ADAR1-dependent TNBC cell lines also exhibit elevated IFN stimulated gene 23 expression. IFNAR1 reduction significantly rescues the proliferative defects of ADAR1 loss. 24These findings establish ADAR1 as a novel therapeutic target for TNBC tumors. 25 26 Keywords: ADAR1, triple-negative breast cancer, RNA editing, Type I IFN, PKR 27 28 65highlighting the therapeutic potential of ADAR1 inhibitors for the treatment of TNBC. 66 Results 67ADAR1 is highly expressed in all breast cancer subtypes 68 Using publicly available data from TCGA (The Cancer Genome Atlas) (Han et al., 2015, 69 Fumagalli et al., 2015, we found that high expression of ADAR1 correlated with poor prognosis 70 of breast cancers ( Figure 1A). Recent studies indicated that ADAR1 promotes tumorigenesis of 71 metaplastic breast cancers, and that high expression of ADAR1 correlates with poor prognosis in 72 basal-like breast cancers (Sagredo et al., 2018, Dave et al., 2017. Since both basal-like and 73 5 metaplastic breast cancers share similar characteristics with TNBC, we sought to determine the 74 importance of ADAR1 in the tumorigenesis of TNBC. By evaluating the TCGA database, we 75 found that while mRNA expression of ADAR1 was higher in TNBC compared to normal, it was 76 not significantly different between TNBC and non-TNBC tumors ( Figure 1B). Additionally, 77 ADAR1 expression was not significantly higher in any one subtype of breast cancer based on 78 PAM50 classification(Lehmann et al., 2016) (Supplemental Figure 1A). This observation is 79 consistent with data from the Cancer Cell Line Encyclopedia (CCLE), which uses both RNA-seq 80 and Reverse Phase Protein Array (RPPA) to determine RNA and protein expression levels in 81 numerous cancer cell lines (Supplemental Figure 1B-C). Data from both the TCGA and CCLE 82 datasets also revealed that both p150 and p110 isoforms of ADAR1 were expressed at similar 83 levels between TNBC and non-TNBC specimen (Supplemental Figure 1D-H), with p110 84 expression being consistently higher than p150 in all samples. Additionally, we assessed p150 85 isoform expression by immunohistochemistry in TNBC and non-TNBC patient tumors, Figure 86 1D. We sought to determine the protein expression level of the ADAR1-p150 isoform in a panel 87 of established breast ca...

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RNA‐editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA

Cited by 22 publications

References 83 publications

Investigation of RNA Editing Sites within Bound Regions of RNA-Binding Proteins

Investigation of RNA Editing Sites within Bound Regions of RNA-Binding Proteins

Deciphering miRNAs’ Action through miRNA Editing

ADAR1 editing dependency in triple-negative breast cancer

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