Site-directed RNA editing: recent advances and open challenges

Abstract

RNA editing by cytosine and adenosine deaminases changes the identity of the edited bases. While cytosines are converted to uracils, adenines are converted to inosines. If coding regions of mRNAs are affected, the coding potential of the RNA can be changed, depending on the codon affected. The recoding potential of nucleotide deaminases has recently gained attention for their ability to correct genetic mutations by either reverting the mutation itself or by manipulating processing steps such as RNA splicing. In contrast to CRISPR-based DNA-editing approaches, RNA editing events are transient in nature, therefore reducing the risk of long-lasting inadvertent side-effects. Moreover, some RNA-based therapeutics are already FDA approved and their use in targeting multiple cells or organs to restore genetic function has already been shown. In this review, we provide an overview on the current status and technical differences of site-directed RNA-editing approaches. We also discuss advantages and challenges of individual approaches.

Decoding RNA Editing Sites Through Transcriptome Analysis in Rice Under Alkaline Stress

“…Current study, reported many RESs, and the statics of altering types demonstrated that RE normally happens as G-A, T-C, C-U, and A-I changes in deciphered areas of cellular organs mRNAs. We found that changes in coding regions of the proteins were found at third and first positions which changed the physiochemical properties of the amino acids ( Khosravi and Jantsch, 2021 ; Din et al, 2022 ). Most of the amino acids were changed to hydrophobic which are agreement to the previous research ( Zhang et al, 2020 ).…”

Cas-Based Systems for RNA Editing in Gene Therapy of Monogenic Diseases: In Vitro and in Vivo Application and Translational Potential

“…In addition to dCas13-ADAR2 DD RNA-editing systems, other RNA-editing systems are currently being actively developed, such as BoxB-λN-ADAR DD , SNAP-tag-ADAR DD , and MCP-MS2-ADAR DD , in which the binding of ADAR DD and gRNA is implemented by the λN peptide, SNAP-tag protein, and MS2 bacteriophage coat-binding protein, respectively ( Fry et al, 2020 ; Khosravi and Jantsch, 2021 ). BoxB-λN-ADAR DD has manifested greater efficiency of editing of point mutations in Mecp mRNA in vivo (∼50%) and in vitro (∼70%) ( Sinnamon et al, 2017 ; Sinnamon et al, 2020 ).…”

Nucleoside analogs in ADAR guide strands targeting 5′-UA̲ sites

“…Since inosine is interpreted as guanosine due to its hydrogen bonding with cytidine, this modification introduced by ADARs can change codon meaning. [1][2][3] Two ADAR genes encode catalytically active ADARs in humans (ADAR encoding ADAR1 proteins and ADARB1 encoding the ADAR2 protein). 4 ADAR1 is expressed in two protein isoforms (p110 and p150) that differ in their N-terminal structures.…”

“…5 Because ADARs require duplex structure for activity, their reaction can be directed to specific adenosines in different transcripts using complementary guide strands which form duplexes at the target sites. 1 This approach is currently being pursued to develop therapeutic guide strands that recruit ADARs to correct disease-causing mutations in RNA. [6][7][8][9][10][11][12] One promising variation on this strategy uses chemically modified oligonucleotides to recruit endogenously expressed human ADARs for directed RNA editing.…”