All I's on the RADAR: role of ADAR in gene regulation

Abstract

Adenosine to inosine (A-to-I) editing is the most abundant form of RNA modification in mammalian cells, which is catalyzed by adenosine deaminase acting on the double-stranded RNA (ADAR) protein family. A-to-I editing is currently known to be involved in the regulation of the immune system, RNA splicing, protein recoding, microRNA biogenesis, and formation of heterochromatin. Editing occurs within regions of double-stranded RNA, particularly within inverted Alu repeats, and is associated with many diseases including cancer, neurological disorders, and metabolic syndromes. However, the significance of RNA editing in a large portion of the transcriptome remains unknown. Here, we review the current knowledge about the prevalence and function of A-to-I editing by the ADAR protein family, focusing on its role in the regulation of gene expression. Furthermore, RNA editing-independent regulation of cellular processes by ADAR and the putative role(s) of this process in gene regulation will be discussed.

LncRNA MEG3 acts a biomarker and regulates cell functions by targeting ADAR1 in colorectal cancer

“…ADAR1, a significant member of the ADAR protein family, has been reported to participate in multiple biological functions, such as cell proliferation and apoptosis[33,34]. There are two major isoforms of ADAR1: An interferon-inducible ADAR1 p150 that contains both the Za and Zb Z-DNA-binding domains and a constitutive ADAR1 p110 that lacks the N-terminal Za Z-DNA-binding domain[35]. ADAR1 has emerged as a biomarker in numerous solid tumors, including gastric cancer and esophageal cancer[36,37].…”

A-to-I editing of Malacoherpesviridae RNAs supports the antiviral role of ADAR1 in mollusks

“…At present, ADAR-editing impacting dsDNA viruses has been reported only on target sequences, like structured lncRNAs [82] or miRNA precursors [67, 82, 83]. The evidence of ADAR self-editing in vertebrates [54] and in few, but important invertebrate species [58, 60, 79], suggests the evolutionary conservation of this post-transcriptional RNA editing process [79]. Conversely, the involvement of ADAR in the antiviral host defense was seldom reported in invertebrates [64, 66].…”

“…The alternative splicing of human ADAR1 results in a long (ADAR1-L, 150 kDa) and in a short form (ADAR-S, 110 kDA), with different cellular distribution: ADAR1-L has been demonstrated to move between cytoplasm and nucleus, whereas ADAR1-S (like ADAR2) has been located in the nucleus [53]. The human genome includes numerous A-to-I editing sites, mostly located in non-coding regions, such as introns and 3′-UTRs, often enriched in Alu repeats, as well as in miRNA precursor regions [54]. Among invertebrates, adenosine deaminase activity was reported in Arthropoda ( Drosophila melanogaster ), Crustacea ( Artemia parthenogenetica ), Nematoda ( Caenorhabditis elegans ) and Cephalopoda ( Octopus bimaculoides ) as well as in the earliest-diverging phyla of Metazoa [55–60].…”

Occurrence and Functions of m6A and Other Covalent Modifications in Plant mRNA

“…The discovery of mRNA modifications in plants is lagging behind that in animal cells, in which at least six additional modifications have been mapped and, in some cases, also functionally analyzed (Boccaletto et al, 2018). These modified nucleotides include inosine (I; Bass and Weintraub, 1988;Shevchenko and Morris, 2018), internal (as opposed to cap) 7-methylguanosine (m 7 G; Zhang et al, 2019b), cap-proximal 29-O,N 6 -dimethyladenosine (m 6 A m ; Wei et al, 1975a;Linder et al, 2015;Mauer et al, 2017;Boulias et al, 2019), N 1 -methyladenosine (m 1 A; Dominissini et al, 2016;Li et al, 2016Li et al, , 2017bSafra et al, 2017), 4-acetylcytidine (ac4C;Arango et al, 2018), 5-hydroxymethylcytidine (hm 5 C; Delatte et al, 2016), and 29-O-methylation (any nucleotide [Nm]; Furuichi et al, 1975;Wei et al, 1975b;Dai et al, 2017;Bartoli et al, 2018). For at least one of these modifications, m 7 G, plant homologs exist of the enzyme responsible for its introduction into tRNA (Alexandrov et al, 2002) and some mRNA sites (Zhang et al, 2019b).…”