To edit or not to edit: regulation of ADAR editing specificity and efficiency

Abstract

Hundreds to millions of adenosine (A)-to-inosine (I) modifications are present in eukaryotic transcriptomes and play an essential role in the creation of proteomic and phenotypic diversity. As adenosine and inosine have different base-pairing properties, the functional consequences of these modifications or 'edits' include altering coding potential, splicing, and miRNA-mediated gene silencing of transcripts. However, rather than serving as a static control of gene expression, A-to-I editing provides a means to dynamically rewire the genetic code during development and in a cell-type specific manner. Interestingly, during normal development, in specific cells, and in both neuropathological diseases and cancers, the extent of RNA editing does not directly correlate with levels of the substrate mRNA or the adenosine deaminase that act on RNA (ADAR) editing enzymes, implying that cellular factors are required for spatiotemporal regulation of A-to-I editing. The factors that affect the specificity and extent of ADAR activity have been thoroughly dissected in vitro. Yet, we still lack a complete understanding of how specific ADAR family members can selectively deaminate certain adenosines while others cannot. Additionally, in the cellular environment, ADAR specificity and editing efficiency is likely to be influenced by cellular factors, which is currently an area of intense investigation. Data from many groups have suggested two main mechanisms for controlling A-to-I editing in the cell: (1) regulating ADAR accessibility to target RNAs and (2) protein-protein interactions that directly alter ADAR enzymatic activity. Recent studies suggest cis- and trans-acting RNA elements, heterodimerization and RNA-binding proteins play important roles in regulating RNA editing levels in vivo. WIREs RNA 2016, 7:113-127. doi: 10.1002/wrna.1319.

Evidence for transcriptome-wide RNA editing among Sus scrofa PRE-1 SINE elements

“…One factor that may contribute to tissue specificity of RNA editing is differential expression of ADAR [20]. Using RNA samples from 33 additional pigs, a quantitative real-time PCR assay was used to infer ADAR transcript abundance differences between liver, subcutaneous fat, and LD muscle (Fig.…”

A-to-I RNA Editing Up-regulates Human Dihydrofolate Reductase in Breast Cancer

“…In this study, knockdown of ADAR2 marginally increased RNA editing levels in the 3'-UTR of DHFR. It is known that homodimerization is important for functions of both human ADAR1 and ADAR2, whereas heterodimerization between ADAR1 and ADAR2 has been shown to decrease editing activity (Deffit and Hundley, 2016). The increased RNA editing levels by ADAR2 knockdown may be due to the increase in functional ADAR1…”

Rett Syndrome: Crossing the Threshold to Clinical Translation

“…In theory, gene or mRNA editing could circumvent problems associated with MeCP2 dosage, since only the mutant MECP2 would be targeted and MeCP2 would retain all of its endogenous regulation [57, 58]. However, development of a translatable gene-editing approach is confounded by the following unresolved issues: (i) the ability to deliver the nuclease and editing template broadly to all cells; (ii) the relatively low efficiency of gene editing in vivo in postmitotic cells; (iii) potential nonspecific nuclease cleavage elsewhere in the genome, especially upon chronic expression of the editing nuclease; and (iv) potential immune responses against the editing nuclease, which would be a nonhuman protein.…”