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A-to-I editing of coding and non-coding RNAs by ADARs

Key Points

  • A-to-I RNA editing is catalysed by adenosine deaminases acting on RNA (ADARs).

  • Three mammalian ADAR genes (ADAR1, ADAR2 and ADAR3) with common functional domains have been identified.

  • Protein-coding sequences of a limited number of genes, such as glutamate receptor GRIA2 and serotonin receptor HTR2C, are edited, resulting in dramatic alterations of protein functions.

  • Deficiencies in A-to-I RNA editing cause human diseases and pathophysiology.

  • Genome-wide screening has identified numerous A-to-I editing sites in inverted Alu repeats located in non-coding regions of mRNAs. Alu editing in these transcripts is likely to affect many cellular processes.

  • The biogenesis and function of certain miRNAs is regulated by editing of the primary miRNAs (pri-miRNAs).

  • ADAR1 forms a complex with Dicer to promote the efficacy of miRNA processing and RNA interference (RNAi) in developing embryos.

Abstract

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. This A-to-I editing occurs not only in protein-coding regions of mRNAs, but also frequently in non-coding regions that contain inverted Alu repeats. Editing of coding sequences can result in the expression of functionally altered proteins that are not encoded in the genome, whereas the significance of Alu editing remains largely unknown. Certain microRNA (miRNA) precursors are also edited, leading to reduced expression or altered function of mature miRNAs. Conversely, recent studies indicate that ADAR1 forms a complex with Dicer to promote miRNA processing, revealing a new function of ADAR1 in the regulation of RNA interference.

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Figure 1: Deamination of adenosine to inosine by adenosine deaminases acting on RNA (ADAR) proteins.
Figure 2: Cellular localization of adenosine deaminases acting on RNA 1 (ADAR1) and ADAR2.
Figure 3: Editing of Alu double-stranded RNAs (dsRNAs) and its consequences.
Figure 4: Regulation of microRNA (miRNA) processing, expression and selectivity by RNA editing.
Figure 5: Regulation of RNA interference (RNAi) by adenosine deaminases acting on RNA (ADARs).

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Acknowledgements

The author thanks John M. Murray for critical reading of the manuscript. This work was supported in part by grants from the U.S. National Institutes of Health, Ellison Medical Foundation, Macula Vision Research Foundation and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.

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DATABASES

National Cancer Institute Drug Dictionary

Online Mendelian Inheritance in Man (OMIM)

ADAR1

ADAR2

ADAR3

RADAR editing sites database

DARNED editing sites database

miRNA editing sites databases

miRBase database

Glossary

Alu

A type of retrotransposon of the short interspersed nuclear elements (SINE) family found in primate genomes. There are about 1.4 million copies of Alu in the human genome.

Z-DNA

A left-handed form of DNA that is different from the common A and B structural isoforms of DNA. Its biological functions are largely unknown.

Deamination

The chemical process that replaces a primary amino group by a hydroxyl group, resulting in conversion of one nucleoside to another.

Inositol hexakisphosphate

(InsP6). An intracellular organic compound that is found throughout the animal kingdom and is affiliated with a wide range of important physiological activities such as modulation of haemoglobin structure and function.

Retrotransposon

A class of genetic elements that includes endogenous retroviruses and transposable elements, which propagate in the genome through an intermediate RNA stage.

Nuclear paraspeckles

Discrete, irregularly shaped nuclear compartments. Usually, approximately 10–30 paraspeckles are present in the interphase mammalian nucleus. Their function is not known, but they may trap certain proteins in the nucleus.

Wobble base pairs

Pairs of nucleotides other than G:C and A:U, such as thermodynamically less stable I:U and G:U pairs. Wobble base pairs, like Watson–Crick base pairs, participate in RNA folding and the formation of secondary structures.

Endogenous short interfering RNAs

(endo-siRNAs). siRNAs derived from endogenous double-stranded transcripts and repetitive elements such as Alu or other retrotransposons.

RNase III protein

A double-stranded RNA (dsRNA)-specific endonuclease that cleaves dsRNA into short fragments with a 3′ overhang and a recessed 5′ phosphate. The RNA interference (RNAi) factors Drosha and Dicer are such proteins.

RNA-induced silencing complex

(RISC). A complex containing short interfering RNAs (siRNAs) or microRNAs (miRNAs) and an Argonaute protein, which mediates the degradation or translation inhibition of target mRNAs that have high sequence complementarity to the small RNAs.

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Nishikura, K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol 17, 83–96 (2016). https://doi.org/10.1038/nrm.2015.4

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