RNA Editors, Cofactors, and mRNA Targets: An Overview of the C-to-U RNA Editing Machinery and Its Implication in Human Disease

Abstract

One of the most prevalent epitranscriptomic modifications is RNA editing. In higher eukaryotes, RNA editing is catalyzed by one of two classes of deaminases: ADAR family enzymes that catalyze A-to-I (read as G) editing, and AID/APOBEC family enzymes that catalyze C-to-U. ADAR-catalyzed deamination has been studied extensively. Here we focus on AID/APOBEC-catalyzed editing, and review the emergent knowledge regarding C-to-U editing consequences in the context of human disease.

A cytosine-to-uracil change within the programmed -1 ribosomal frameshift signal of SARS-CoV-2 results in structural similarities with the MERS-CoV signal

“…The deamination of cytosine into uracil is mediated by the cytidine deaminase APOBEC (Apolipoprotein B mRNA Editing Catalytic Polypeptide-like) family of proteins 42,43 . APOBECs are responsible for widespread C-to-U RNA editing of cellular transcripts.…”

“…APOBEC1 is expressed in the liver, and a shorter isoform that results from mRNA editing is detected in the small intestine. APOBECs display different sequence requirements around the target C. In SARS-CoV-2, bases flanking the C 13536 to U mutation site match the consensus sequence of cal sequences 97.2% Ambiguous 1.2% Other 0.5% (Figure 4) 42,45 . A second RNA element important for editing is an 11-nucleotide mooring sequence downstream of the target C. In SARS-CoV-2, the similarity with the consensus mooring sequence of APOBEC1 is only partial.…”

“…When nsp14-ExoN is inactivated, the spectrum of mutations introduced by the Nsp12 RNA-dependent RNA polymerase becomes apparent 49 . As the C-to-U transition is not a frequent change introduced by the polymerase, it is possible that it originates from RNA editing by a cytosine deaminase 35,42,43 . Biophysical single-molecule assays and kinetics studies on ensembles revealed how the interplay between the conformational plasticity of RNA-inducing frameshifting structures and the dynamics of the ribosome play a critical role in the -1 PRF mechanism [50][51][52][53][54] .…”

Deciphering miRNAs’ Action through miRNA Editing

“…The AID/APOBEC family includes several enzymes sharing a similar structure but differing in terms of function, with only few of them, i.e., APOBEC1, APOBEC3A and APOBEC3G, having C-to-U RNA editing activities [29,[46][47][48]. Similarly to ADAR proteins, APOBECs have different intracellular distributions.…”

“…In contrast to APOBEC1, APOBEC3A and 3G are expressed in most tissues (Figure 2a), but APOBEC1 is the most well characterized isoform of the AID/APOBEC family [50]. Loss of APOBEC1 does not alter embryonic development but it impairs lipoprotein metabolism by editing apolipoprotein B (apoB) RNA and it affects neurological function [48][49][50][51]. In contrast to information collected from DICE database (Figure 2b), the APOBEC1 deaminase was reported to be significantly expressed in immune cells, where it exerts RNA editing activity on 3 -UTRs of numerous mRNAs [48,50,52].…”