RNA-interacting proteins act as site-specific repressors of ADAR2-mediated RNA editing and fluctuate upon neuronal stimulation

Tariq, Aamira; Garncarz, Wojciech; Handl, Cornelia; Balík, Aleš; Pusch, Oliver; Jantsch, Michael F.

doi:10.1093/nar/gks1353

Cited by 74 publications

(82 citation statements)

References 43 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, ADAR3 is specifically expressed in the brain and central nervous system (16,28) and may act as one of many brain-specific regulators of editing. Recently, several RBPs including SRFS9 and RPS14 were shown to alter editing of specific target mRNAs, and expression of these RBPs changed during embryonic development as well as upon neuronal stimulation (54). An interesting possibility is that ADAR3 expression varies during development or in specific brain regions and results in differential GRIA2 editing in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…However, editing by ADARs is also regulated on the transcript level by the landscape of RNA-binding proteins present on a given mRNA. For example, the RNA-binding proteins SRFS9, RPS14, and DDX15 were shown to inhibit RNA editing of specific target mRNAs (54). Interestingly, these proteins decrease in expression during brain development in mice, and the expression levels of SFRS9 and DDX15 are altered upon neuronal stimulation.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

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...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

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

“…Recently, it was shown that in developing mouse neurons increased nuclear localization of ADAR2 might contribute to this phenomenon [29] together with protein modifications on ADARs and regulatory factors [30,31]. We previously showed that a gradual increase in editing is also found for filamin A, in both neuronal and non-neuronal tissues [20].…”

Section: Discussionmentioning

confidence: 99%

“…At this point we cannot exclude that ADAR2 activity on this specific transcript could be at least in part a regulated process. As there is no correlation between Flnb editing and ADAR2 expression, editing of Flnb could possibly be affected by competing RNA-binding proteins or editing regulators [24,30,31,37]. This idea is also supported by the lack of correlation of editing levels in Flna and Flnb RNAs which are both edited by ADAR2.…”

Section: Discussionmentioning

confidence: 99%

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

et al. 2018

Self Cite

View full text Add to dashboard Cite

Adenosine to inosine RNA editing in protein-coding messenger RNAs (mRNAs) potentially leads to changes in the amino acid composition of the encoded proteins. The mRNAs encoding the ubiquitously expressed actin-crosslinking proteins Filamin A and Filamin B undergo RNA editing leading to a highly conserved glutamine to arginine exchange at the identical position in either protein. Here, by targeted amplicon sequencing we analysed the RNA editing of Filamin B across several mouse tissues during post-natal development. We find highest filamin B editing levels in skeletal muscles, cartilage and bones, tissues where Filamin B function seems most important. Through the analysis of Filamin B editing in mice deficient in either ADAR1 or 2, we identified ADAR2 as the enzyme responsible for Filamin B RNA editing. We show that in neuronal tissues Filamin B editing drops in spliced transcripts indicating regulated maturation of edited transcripts. We show further that the variability of Filamin B editing across several organs correlates with its mRNA expression.

show abstract

“…Alternative splicing of ADAR transcripts (Lai et al 1997;Rueter et al 1999) and post-transcriptional modification (Desterro et al 2005) have both been observed to cause decreased ADAR activity. In addition, RNA-binding proteins can both promote and repress editing of specific adenosines (Bhogal et al 2011;Tariq et al 2013;Washburn et al 2014). However, how much these mechanisms interact to determine overall editing efficiency and whether these mechanisms are active in all cell types is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans

Washburn

Hundley

2016

RNA

View full text Add to dashboard Cite

Adenosine-to-inosine RNA editing by ADARs affects thousands of adenosines in an organism's transcriptome. However, adenosines are not edited at equal levels nor do these editing levels correlate well with ADAR expression levels. Therefore, additional mechanisms are utilized by the cell to dictate the editing efficiency at a given adenosine. To examine cis-and transacting factors that regulate A-to-I editing levels specifically in neural cells, we utilized the model organism Caenorhabditis elegans. We demonstrate that a double-stranded RNA (dsRNA) binding protein, ADR-1, inhibits editing in neurons, which is largely masked when examining editing levels from whole animals. Furthermore, expression of ADR-1 and mRNA expression of the editing target can act synergistically to regulate editing efficiency. In addition, we identify a dsRNA region within the Y75B8A.8 3 ′ UTR that acts as a cis-regulatory element by enhancing ADR-2 editing efficiency. Together, this work identifies mechanisms that regulate editing efficiency of noncoding A-to-I editing sites, which comprise the largest class of ADAR targets.

show abstract

RNA-interacting proteins act as site-specific repressors of ADAR2-mediated RNA editing and fluctuate upon neuronal stimulation

Cited by 74 publications

References 43 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

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans

Contact Info

Product

Resources

About