RNA editing in the forefront of epitranscriptomics and human health

Abstract

Post-transcriptional modifications have been recently expanded with the addition of RNA editing, which is predominantly mediated by adenosine and cytidine deaminases acting on DNA and RNA. Here, we review the full spectrum of physiological processes in which these modifiers are implicated, among different organisms. Adenosine to inosine (A-to-I) editors, members of the ADAR and ADAT protein families are important regulators of alternative splicing and transcriptional control. On the other hand, cytidine to uridine (C-to-U) editors, members of the AID/APOBEC family, are heavily implicated in innate and adaptive immunity with important roles in antibody diversification and antiviral response. Physiologically, these enzymes are present in the nucleus and/or the cytoplasm, where they modify various RNA molecules, including miRNAs, tRNAs apart from mRNAs, whereas DNA editing is also possible by some of them. The expansion of next generation sequencing technologies provided a wealth of data regarding such modifications. RNA editing has been implicated in various disorders including cancer, and neurological diseases of the brain or the central nervous system. It is also related to cancer heterogeneity and the onset of carcinogenesis. Response to treatment can also be affected by the RNA editing status where drug efficacy is significantly compromised. Studying RNA editing events can pave the way to the identification of new disease biomarkers, and provide a more personalised therapy to various diseases.

Keywords: ADAR; AID; APOBEC; Cancer; Cytidine/adenosine deaminases; Epitranscriptomics; Post-transcriptional modifications; RNA editing.

Fig. 1

Cytidine and adenosine deaminases are critical RNA editors that play important functions in physiological events. a The vital role of APOBEC1 editing can be observed in the production of apolipoprotein B in the gut. The C-to-U editing at residue 2153 of hepatic Apo-B100 transforms the glutamate to a stop codon and produces a truncated protein Apo-B48 in intestinal cells [4]. b In neurons, mRNA editing of the glutamate receptor 2 (GluR2) at position 607 by ADAR2 results in an adenosine to inosine chance. This transforms the CAG codon for glutamine (Q) to CIG for arginine (R) as (CGG), since ribosomes read inosine (I) as guanosine (G). This neutralizes the diffusion of divalent cations and makes the receptor impermeable to calcium [112]

Fig. 2

Human cytidine and adenosine deaminase family members. a The cytidine deaminase AID/APOBECs family is shown. Activation-induced cytidine deaminase (AID or AICDA) and all apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like (APOBECs) have one catalytically active cytidine or deoxycytidine deaminase domain (ZDD). APOBEC3 diversifies in 7 submembers (APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, APOBEC3H) whereas some have dual deaminase domain structures but the one in the N terminus is catalytically inactive. b The adenosine deaminase ADARs, ADATs and ADADs families are shown. Three members of the adenosine deaminase acting on RNAs (ADAR1, ADAR2, ADAR3). Two isoforms are known for ADAR1, ADAR1-p150 and ADAR1-p110 and harbour Z-DNA-binding domains. ADAR3 has a unique arginine-rich R domain. Three members of the adenosine deaminase acting on tRNAs (ADAT1, ADAT2 ADAT3). Up to three repeats of the dsRNA binding domain (dsRBD) and a catalytic deaminase domain are present in adenosine deaminases. Two adenosine deaminase domain-containing proteins (ADAD1, ADAD2) are also known as TENR and TENRL respectively. Amino acid length and motifs retrieved from UniProt database [198]. Length is not drawn to scale

Fig. 3

Functional roles of RNA editing. Adenosine and cytidine deaminases target RNAs molecules and modify their sequence affecting multiple processes. A-to-I or C-to-U modifications in RNA transcripts are reflected in the folding of the RNA structure influencing its structural stability and binding accessibility for further processing [199]. mRNA abundance and gene expression is regulated by miRNA or miRNA target editing, influencing gene silencing by RNA degradation [84, 156]. Protein diversity is another outcome of RNA editing since it can create or abolish splicing sites regulating alternative splicing [54]. Moreover, editing in coding regions can recode amino acids and create an alternative protein with distinct functionalities [4]. Recoding protein example was built with SWISS-MODEL workspace [200]