ADAR RNA editing below the backbone

Keegan, Liam P.; Khan, Aalia; Vukić, Dragana; O’Connell, Mary A.

doi:10.1261/rna.060921.117

Cited by 22 publications

(148 citation statements)

References 81 publications

(129 reference statements)

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“…6g). We did not observe any significant difference in ref (2)p levels between head extracts of Adar 5G1 mutant, Adar 5G1 ; ChAT > Hsc70-4 or Adar 5G1 ; ChAT > Sgt RNAi flies. This suggests that, as expected, increased Hsc70-4 does not increase canonical autophagy or significantly change levels of ref (2)p.…”

Section: Rescue Of Adar Mutant Phenotypes By Increased Expression Of contrasting

confidence: 70%

“…4a-d), even though it may also be somewhat impaired in Adar 5G1 . Immunoblots show that ref (2)p protein, the Drosophila homolog of the vertebrate p62 adapter for canonical autophagy of ubiquitinated proteins, is increased in Adar 5G1 and increased much more with reduced Tor or increased Atg5 (Fig. 4e).…”

Section: Discussionmentioning

confidence: 99%

“…To assess canonical autophagy in the Adar 5G1 mutant and rescues, we examined levels of ref(2)p protein. ref (2)p is the Drosophila orthologue of the mammalian p62 canonical autophagy adapter protein (also called Sequestosome1) that brings ubiquitinated cargo to canonical autophagosomes; p62 is degraded in the process and p62 accumulates when canonical autophagy is defective [44]. If canonical autophagy is operating normally in Adar 5G1 and increased in heads of Adar 5G1 ; Tor k17004 /+ double mutant or Adar 5G1 ; ChAT>Atg5 flies, then levels of p62 protein should be normal in Adar 5G1 and reduced in the double mutants [45].…”

Section: Increased Autophagic Vesicles But Incomplete Clearance Of Rementioning

confidence: 99%

“…In both vertebrates and Drosophila, ADAR RNA editing in CNS transcripts is targeted to pre-mRNA exons that form RNA duplexes with flanking intron sequences. Editing events are frequently located in coding regions, leading to the generation of alternative edited and unedited isoforms of CNS proteins (for review [2]). ADAR2 in mammals is required for editing a glutamine codon to arginine at the Gria2 Q/R site in the transcript encoding a key glutamate receptor subunit [3].…”

Section: Introductionmentioning

confidence: 99%

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Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy

et al. 2020

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Background: In fly brains, the Drosophila Adar (adenosine deaminase acting on RNA) enzyme edits hundreds of transcripts to generate edited isoforms of encoded proteins. Nearly all editing events are absent or less efficient in larvae but increase at metamorphosis; the larger number and higher levels of editing suggest editing is most required when the brain is most complex. This idea is consistent with the fact that Adar mutations affect the adult brain most dramatically. However, it is unknown whether Drosophila Adar RNA editing events mediate some coherent physiological effect. To address this question, we performed a genetic screen for suppressors of Adar mutant defects. Adar 5G1 null mutant flies are partially viable, severely locomotion defective, aberrantly accumulate axonal neurotransmitter pre-synaptic vesicles and associated proteins, and develop an age-dependent vacuolar brain neurodegeneration.Results: A genetic screen revealed suppression of all Adar 5G1 mutant phenotypes tested by reduced dosage of the Tor gene, which encodes a pro-growth kinase that increases translation and reduces autophagy in well-fed conditions. Suppression of Adar 5G1 phenotypes by reduced Tor is due to increased autophagy; overexpression of Atg5, which increases canonical autophagy initiation, reduces aberrant accumulation of synaptic vesicle proteins and suppresses all Adar mutant phenotypes tested. Endosomal microautophagy (eMI) is another Tor-inhibited autophagy pathway involved in synaptic homeostasis in Drosophila. Increased expression of the key eMI protein Hsc70-4 also reduces aberrant accumulation of synaptic vesicle proteins and suppresses all Adar 5G1 mutant phenotypes tested.Conclusions: These findings link Drosophila Adar mutant synaptic and neurotransmission defects to more general cellular defects in autophagy; presumably, edited isoforms of CNS proteins are required for optimum synaptic response capabilities in the brain during the behaviorally complex adult life stage.

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Section: Rescue Of Adar Mutant Phenotypes By Increased Expression Of contrasting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Increased Autophagic Vesicles But Incomplete Clearance Of Rementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy

et al. 2020

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“…Mammalian RNA editing encompasses a process in which select sequences within the original genomic template are enzymatically altered to produce a change in the corresponding RNA transcript (for review, see Gagnidze et al 2018). By far the most prevalent form of RNA editing is adenosine to inosine deamination (A-to-I), which is mediated by members of the family of adenosine deaminases acting on RNA (ADARs) (for review, see Nishikura 2010; Keegan et al 2017). ADAR-mediated RNA editing requires optimal configuration of sites within a double-stranded RNA substrate, most typically residing within intronic or intergenic regions enriched in Alu repeats (Nishikura 2010).…”

Section: Introductionmentioning

confidence: 99%

Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver

Blanc

Xie

Kennedy

et al. 2018

RNA

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Mammalian C to U RNA is mediated by APOBEC1, the catalytic deaminase, together with RNA binding cofactors (including A1CF and RBM47) whose relative physiological requirements are unresolved. Although A1CF complements APOBEC1 for in vitro RNA editing, A1cf -/mice exhibited no change in apolipoproteinB (apoB) RNA editing, while Rbm47 mutant mice exhibited impaired intestinal RNA editing of apoB as well as other targets. Here we examined the role of A1CF and RBM47 in adult mouse liver and intestine, following deletion of either one or both gene products and also following forced (liver or intestinal) transgenic A1CF expression. There were minimal changes in hepatic and intestinal apoB RNA editing in A1cf -/mice and no changes in either liver-or intestine-specific A1CF transgenic mice. Rbm47 liver-specific knockout (Rbm47 LKO ) mice demonstrated reduced editing in a subset (11 of 20) of RNA targets, including apoB. By contrast, apoB RNA editing was virtually eliminated (<6% activity) in intestine-specific (Rbm47 IKO ) mice with only five of 53 targets exhibiting C-to-U RNA editing. Double knockout of A1cf and Rbm47 in liver (AR LKO ) eliminated apoB RNA editing and reduced editing in the majority of other targets, with no changes following adenoviral APOBEC1 administration. Intestinal double knockout mice (AR IKO ) demonstrated further reduced editing (<10% activity) in four of five of the residual APOBEC1 targets identified in AR IKO mice. These data suggest that A1CF and RBM47 each function independently, yet interact in a tissue-specific manner, to regulate the activity and site selection of APOBEC1 dependent C-to-U RNA editing.

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Messenger RNA in Eukaryotes

Akusjärvi

Punga

2017

Encyclopedia of Life Sciences

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The concept that eukaryotic gene expression is primarily regulated at the level of RNA (ribonucleic acid) polymerase II recruitment to a promoter has changed dramatically during the past decades. Changes such as mRNA capping, splicing, polyadenylation, editing as well as various chemical modifications produce a huge variety of unique mRNA species. The mRNA factory model suggests that transcription and mRNA processing are intimately coupled. Thus, the elongating RNA polymerase II, via its carboxy‐terminal domain (CTD), recruits key factors required for the proper capping, splicing and polyadenylation to the nascent transcript. Furthermore, factors controlling the speed of elongation, such as nucleosome occupancy and modification, also partake in the generation of alternatively spliced mRNA, a process that represents an important regulatory level at which eukaryotes can expand the coding capacity of their genomes. Key Concepts mRNA processing events, such as capping, splicing and polyadenylation, are coordinated and occur predominantly co‐transcriptionally. Different phosphorylation patterns of the carboxy‐terminal domain (CTD) control the temporal recruitment of capping, splicing and polyadenylation factors to the elongating RNA polymerase II. Nucleosomes are preferentially found at exonic sequences and influence the speed of elongation and outcome of co‐transcriptional splicing. Essentially, all eukaryotic genes produce alternatively spliced and polyadenylated mRNAs. Alternative splicing greatly expands the coding capacity of a gene; that is one gene does not only code for one protein. mRNA splicing, mRNA export and nonsense‐mediated mRNA decay are tightly coupled reactions that ensure that erroneous mRNAs are destroyed. RNA editing is an important regulatory mechanism to produce protein diversity and control various aspects of the mRNA life cycle. Dynamic ribonucleotide modifications, such as adenosine methylation, present a novel way to regulate mRNA stability, localisation and translation.

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ADAR RNA editing below the backbone

Cited by 22 publications

References 81 publications

Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy

Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy

Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver

Messenger RNA in Eukaryotes

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