RNA rewriting, recoding, and rewiring in human disease

Zipeto, M; Jiang, Qingfei; Melese, Etienne; Jamieson, Catriona

doi:10.1016/j.molmed.2015.07.001

Cited by 58 publications

(60 citation statements)

References 106 publications

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“…Mutations in ADARs have been shown to contribute to disease including Aicardi-Goutières syndrome and dyschromatosis symmetrica hereditaria, and aberrant RNA editing has been implicated in prostate cancer, hepatocellular carcinoma, and chronic myeloid leukemia (19,32,33 …”

Section: Edited By Charles E Samuelmentioning

confidence: 99%

Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma

Oakes¹,

Anderson

Cohen-Gadol

et al. 2017

Journal of Biological Chemistry

149

115

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Edited by Charles E. SamuelRNA editing is a cellular process that precisely alters nucleotide sequences, thus regulating gene expression and generating protein diversity. Over 60% of human transcripts undergo adenosine to inosine RNA editing, and editing is required for normal development and proper neuronal function of animals. Editing of one adenosine in the transcript encoding the glutamate receptor subunit B, glutamate receptor ionotropic AMPA 2 (GRIA2), modifies a codon, replacing the genomically encoded glutamine (Q) with arginine (R); thus this editing site is referred to as the Q/R site. Editing at the Q/R site of GRIA2 is essential, and reduced editing of GRIA2 transcripts has been observed in patients suffering from glioblastoma. In glioblastoma, incorporation of unedited GRIA2 subunits leads to a calcium-permeable glutamate receptor, which can promote cell migration and tumor invasion. In this study, we identify adenosine deaminase that acts on RNA 3 (ADAR3) as an important regulator of Q/R site editing, investigate its mode of action, and detect elevated ADAR3 expression in glioblastoma tumors compared with adjacent brain tissue. Overexpression of ADAR3 in astrocyte and astrocytoma cell lines inhibits RNA editing at the Q/R site of GRIA2. Furthermore, the double-stranded RNA binding domains of ADAR3 are required for repression of RNA editing. As the Q/R site of GRIA2 is specifically edited by ADAR2, we suggest that ADAR3 directly competes with ADAR2 for binding to GRIA2 transcript, inhibiting RNA editing, as evidenced by the direct binding of ADAR3 to the GRIA2 pre-mRNA. Finally, we provide evidence that both ADAR2 and ADAR3 expression contributes to the relative level of GRIA2 editing in tumors from patients suffering from glioblastoma.Adenosine deaminases that act on RNA (ADARs) 2 catalyze the hydrolytic deamination of adenosine residues within double-stranded RNA (dsRNA) structures that form by base pairing of nearby complementary sequences (1-3). This RNA editing event creates a non-canonical nucleoside, inosine, which base pairs similarly to guanosine (4). RNA editing affects gene expression through modification of codons to create novel protein isoforms (5). Furthermore, editing can alter microRNA and siRNA binding sites, splice acceptor or splice donor sites, or RNA structure and stability (6 -9). A majority of the targets of RNA editing are found in the nervous system, and RNA editing is critical for maintaining proper neuronal function (10). Furthermore, transcripts encoding proteins involved in neurotransmission are often targets of RNA editing, which alters the protein amino acid sequence and physiological function of these ion channels and receptors (11,12).In mammals, three ADAR proteins, ADAR1, ADAR2, and ADAR3, and two ADAR-like proteins, ADAD1 and ADAD2, have been identified (13-17). The ADAR and ADAR-like protein family members contain several common modular domains that are important for function (18,19). Most strikingly, the human ADAR and ADAR-like proteins contain at least one ds...

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Section: Edited By Charles E Samuelmentioning

confidence: 99%

Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma

Oakes¹,

Anderson

Cohen-Gadol

et al. 2017

Journal of Biological Chemistry

149

115

View full text Add to dashboard Cite

show abstract

“…[6][7][8][9] In humans, the ADAR family comprises ADAR1, ADAR2 and ADAR3, which share repeated copies of dsRNA-binding domains and a catalytic adenosine deaminase domain. 10 Among them, ADAR1 is the major contributor to RNA editing in cancer, especially in breast. Anantharaman et al 11 have demonstrated that breast cancer cells show elevated ADAR1 but reduced ADAR2 mRNA levels compared to normal cells.…”

Section: Introductionmentioning

confidence: 99%

“…7 RNA sequencing analysis has revealed that ADAR1 is among the top 5% of upregulated genes in relapsed lobular breast cancer. 10 Fumagalli et al 7 have demonstrated elevated ADAR expression in breast cancer compared with that in matched normal tissues, which occurs because of an aberrantly high copy number. They have also demonstrated that ADAR expression and editing are associated with type I interferon response in the tumour environment.…”

Section: Introductionmentioning

confidence: 99%

ADAR1 expression is associated with tumour-infiltrating lymphocytes in triple-negative breast cancer

et al. 2017

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Tumours with a high mutation burden exhibit considerable neoantigens and tumour-infiltrating lymphocytes. RNA editing by ADAR1 is a source of changes in epitope. However, ADAR1 expression in cancer cells and tumour-infiltrating lymphocyte levels in triple-negative breast cancer have not been well evaluated. We immunohistochemically examined ADAR1 expression in 681 triple-negative breast cancer patients and analysed their clinicopathological characteristics. We also analysed basal-like tumours using The Cancer Genome Atlas data. Among the 681 triple-negative breast cancer patients, 45.8% demonstrated high ADAR1 expression. Tumours with high ADAR1 expression exhibited high tumourinfiltrating lymphocyte levels, considerable CD8 + T lymphocyte infiltration, high histological grade and high expression of interferon-related proteins, including HLA-ABC, MxA and PKR. Among patients with lymph node metastasis, those with high tumour-infiltrating lymphocyte levels and low ADAR1 expression demonstrated the best disease-free survival. The Cancer Genome Atlas data analysis of basal-like tumours revealed significant positive correlation between ADAR1 and CD8B expression and positive association of high ADAR1 expression with immune responses and apoptosis pathways. We detected high ADAR1 expression in half of the triple-negative breast cancer patients. In addition to DNA mutations, RNA editing can be related to neoantigens; hence, we need to explore non-synonymous mutations exclusively found using RNA sequencing data to identify clinically relevant neoantigens.

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“…These enzyme-catalyzed transformations include inserting, deleting, converting or modifying ribonucleotides. 1,2 One of the most abundant RNA modifications found in metazoans is the deamination of adenosine to inosine (A-to-I). This reaction is catalyzed by the class of enzymes called adenosine deaminases acting on RNA (ADAR).…”

Section: Introductionmentioning

confidence: 99%

Effects of Aicardi-Goutières syndrome mutations predicted from ADAR-RNA structures

Fisher

Beal

2017

RNA Biology

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Adenosine (A) to inosine (I) RNA editing is important for life in metazoan organisms. Dysregulation or mutations that compromise the efficacy of A to I editing results in neurological disorders and a shorten life span. These reactions are catalyzed by adenosine deaminases acting on RNA (ADARs), which hydrolytically deaminate adenosines in regions of duplex RNA. Because inosine mimics guanosine in hydrogen bonding, this prolific RNA editing alters the sequence and structural information in the RNA landscape. AicardiGouti eres syndrome (AGS) is a severe childhood autoimmune disease that is one of a broader set of inherited disorders characterized by constitutive upregulation of type I interferon (IFN) referred to as type I interferonopathies. AGS is caused by mutations in multiple genes whose protein products, including ADAR1, are all involved in nucleic acid metabolism or sensing. The recent crystal structures of human ADAR2 deaminase domain complexed with duplex RNA substrates enabled modeling of how AGS causing mutations may influence RNA binding and catalysis. The mutations can be broadly characterized into three groups; mutations on RNA-binding loops that directly affect RNA binding, "second-layer" mutations that can alter the disposition of RNA-binding loops, and mutations that can alter the position of an a-helix bearing an essential catalytic residue.

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RNA rewriting, recoding, and rewiring in human disease

Cited by 58 publications

References 106 publications

Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma

Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma

ADAR1 expression is associated with tumour-infiltrating lymphocytes in triple-negative breast cancer

Effects of Aicardi-Goutières syndrome mutations predicted from ADAR-RNA structures

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