A-to-I RNA Editing in Cancer: From Evaluating the Editing Level to Exploring the Editing Effects

Abstract

As an important regulatory mechanism at the posttranscriptional level in metazoans, adenosine deaminase acting on RNA (ADAR)-induced A-to-I RNA editing modification of double-stranded RNA has been widely detected and reported. Editing may lead to non-synonymous amino acid mutations, RNA secondary structure alterations, pre-mRNA processing changes, and microRNA-mRNA redirection, thereby affecting multiple cellular processes and functions. In recent years, researchers have successfully developed several bioinformatics software tools and pipelines to identify RNA editing sites. However, there are still no widely accepted editing site standards due to the variety of parallel optimization and RNA high-seq protocols and programs. It is also challenging to identify RNA editing by normal protocols in tumor samples due to the high DNA mutation rate. Numerous RNA editing sites have been reported to be located in non-coding regions and can affect the biosynthesis of ncRNAs, including miRNAs and circular RNAs. Predicting the function of RNA editing sites located in non-coding regions and ncRNAs is significantly difficult. In this review, we aim to provide a better understanding of bioinformatics strategies for human cancer A-to-I RNA editing identification and briefly discuss recent advances in related areas, such as the oncogenic and tumor suppressive effects of RNA editing.

Keywords: ADAR; RNA editing; cancer; circular RNAs; non-coding RNA.

Figure 1

ADARs and RNA editing effects. (A) There are three main proteins of ADAR enzymes, ADAR1 (p110 and p150), ADAR2, and ADAR3. Vertebrate ADARs share a conserved deaminase domain and two to three dsRNA-binding domains (dsRBDs). In addition, ADAR1 p110 and p150 have similar Z-DNA-binding domains. ADAR3 is unique since its deaminase domain is catalytically inactive, and it also has an arginine-rich domain (R). (B) RNA editing in gene coding regions may introduce protein mutations. (C) Binding ADARs to certain dsRNAs may affect the RNA structure, thereby altering RNA biological processing and stability. (D) ADAR1 binds and inhibits the generation of circular RNAs. (E) microRNA (miRNA) or 3’ UTR editing may change or redirect the interactive relationship between certain UTRs and miRNAs. (F) RNA editing sites were identified in all three main regions involved with pre-mRNA alternative splicing (donor: 5’ splicing site, acceptor: 3’ splicing site and branch site), and pre-mRNA intron editing may contribute to pre-mRNA alternative splicing.

Figure 2

Optimized editing sites identification strategies for cancer research. This flow chart is briefly regarding the content of Improvements in Editing Site Calling for Cancer Research.