ADAR enzyme and miRNA story: a nucleotide that can make the difference

Abstract

Adenosine deaminase acting on RNA (ADAR) enzymes convert adenosine (A) to inosine (I) in double-stranded (ds) RNAs. Since Inosine is read as Guanosine, the biological consequence of ADAR enzyme activity is an A/G conversion within RNA molecules. A-to-I editing events can occur on both coding and non-coding RNAs, including microRNAs (miRNAs), which are small regulatory RNAs of ~20-23 nucleotides that regulate several cell processes by annealing to target mRNAs and inhibiting their translation. Both miRNA precursors and mature miRNAs undergo A-to-I RNA editing, affecting the miRNA maturation process and activity. ADARs can also edit 3' UTR of mRNAs, further increasing the interplay between mRNA targets and miRNAs. In this review, we provide a general overview of the ADAR enzymes and their mechanisms of action as well as miRNA processing and function. We then review the more recent findings about the impact of ADAR-mediated activity on the miRNA pathway in terms of biogenesis, target recognition, and gene expression regulation.

Figure 1

Structure of ADAR family proteins: ADAR1, ADAR2, and ADAR3. The ADAR enzymes contain a C-terminal conserved catalytic deaminase domain (DM), two or three dsRBDs in the N-terminal portion. ADAR1 full-length protein also contains a N-terminal Zα domain with a nuclear export signal (NES) and a Zβ domain, while ADAR3 has a R-domain. A nuclear localization signal is also indicated.

Figure 2

Schematic diagram of the miRNA genes. (A) Monocistronic intergenic miRNA gene; (B) Monocistronic exonic/intronic miRNA gene.

Figure 3

miRNA biogenesis and processing. Canonical biogenesis of pri-miRNA transcription is mediated by Pol II. Next, the microprocessor complex composed of Drosha and DGCR8 mediates the nuclear cleavage of pri-miRNA into pre-miRNA. The nuclear export of pre-miRNA is subsequently mediated by exportin-5/Ran-GTP61. Cytoplasmic pre-miRNA is processed by Dicer into a duplex microRNA. The next step is the unwinding of the duplex into a mature ~22 nucleotide miRNA and a miRNA* by the RISC complex. The mature miRNA is generally conveyed by the RISC on the targeted mRNA, whilst miRNA* can be degraded or alternatively perform a different targeting.

Figure 4

Editing-dependent effects of ADARs on miRNA pathway. miRNA precursors (pri- and pre-miRs) undergo specific A-to-I RNA editing that (i) may block their maturation process at either Drosha or Dicer step; (ii) may affect the loading of the edited miRNA to the RISC complex; (iii) may redirect the edited miRNA to a new set of target mRNAs.