ADAR RNA editing in innate immune response phasing, in circadian clocks and in sleep

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Authors	SINIGAGLIA Ketty WIATREK Dagmara KHAN Anzer MICHALÍK David SAMBRANI Nagraj SEDMÍK Jiří VUKIĆ Dragana O'CONNELL Mary Anne KEEGAN Liam
Year of publication	2019
Type	Article in Periodical
Magazine / Source	Biochimica et biophysica acta - Gene regulatory mechanisms
MU Faculty or unit	Central European Institute of Technology
Citation
Web	Full Text
Doi	http://dx.doi.org/10.1016/j.bbagrm.2018.10.011
Keywords	ADAR; RNA editing; dsRNA; microRNA; Epitranscriptome; Innate immunity; Circadian rhythm; Sleep
Description	Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in dsRNA. ADAR editing in premRNAs recodes open reading frames and alters splicing, mRNA structure and interactions with miRNAs. Here, we review ADAR gene expression, splice forms, posttranslational modifications, subcellular localizations and functions of ADAR protein isoforms. ADAR1 edits cellular dsRNA to prevent aberrant activation of cytoplasmic antiviral dsRNA sensors; ADAR1 mutations lead to aberrant expression of interferon in Aicardi Goutieres syndrome (AGS), a human congenital encephalopathy. We review related studies on mouse Adarl mutant phenotypes, their rescues by preventing signaling from the antiviral RIG-I-like Sensors (RLRs), as well as Marl mechanisms in innate immune suppression and other roles of Adarl, including editing-independent effects. ADAR2, expressed primarily in CNS, edits glutamate receptor transcripts; regulation of ADAR2 activity in response to neuronal activity mediates homeostatic synaptic plasticity of vertebrate AMPA and kainite receptors. In Drosophila, synapses and synaptic proteins show dramatic decreases at night during sleep; Drosophila Adar, an orthologue of ADAR2, edits hundreds of mRNAs; the most conserved editing events occur in transcripts encoding synapse-associated proteins. Adar mutant flies exhibit locomotion defects associated with very increased sleep pressure resulting from a failure of homeostatic synaptic processes. A study on Adcir2 mutant mice identifies a new role in circadian rhythms, acting indirectly through miRNAs such as let-7 to modulate levels of let-7 target mRNAs; ADAR1 also regulates let-7 miRNA processing. Drosophila ADAR, an orthologue of vertebrate ADAR2, also regulates let-7 miRNA levels and Adar mutant flies have a circadian mutant phenotype.
Related projects:	The ERA Chair Culture as a Catalyst to Maximize the Potential of CEITEC Integrative studies of molecular mechanisms of mammalian epitranscriptome