A-to-I RNA editing — immune protector and transcriptome diversifier

Abstract

Modifications of RNA affect its function and stability. RNA editing is unique among these modifications because it not only alters the cellular fate of RNA molecules but also alters their sequence relative to the genome. The most common type of RNA editing is A-to-I editing by double-stranded RNA-specific adenosine deaminase (ADAR) enzymes. Recent transcriptomic studies have identified a number of ‘recoding’ sites at which A-to-I editing results in non-synonymous substitutions in protein-coding sequences. Many of these recoding sites are conserved within (but not usually across) lineages, are under positive selection and have functional and evolutionary importance. However, systematic mapping of the editome across the animal kingdom has revealed that most A-to-I editing sites are located within mobile elements in non-coding parts of the genome. Editing of these non-coding sites is thought to have a critical role in protecting against activation of innate immunity by self-transcripts. Both recoding and non-coding events have implications for genome evolution and, when deregulated, may lead to disease. Finally, ADARs are now being adapted for RNA engineering purposes.

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Fig. 1: A-to-I RNA editing is catalysed by ADAR enzymes and is the most common type of RNA editing in Metazoa.
Fig. 2: A-to-I RNA editing and how it is detected.
Fig. 3: Editing can modify protein function, generate new protein products, alter gene regulation and provide immune protection against endogenous dsRNAs.
Fig. 4: Extent and consequences of editing in repetitive elements.
Fig. 5: RNA editing generates transcriptomic diversity.
Fig. 6: Capacity and limitations of RNA editing as a means for adaptation.
Fig. 7: Utilizing ADARs for RNA probing and engineering.

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Acknowledgements

The authors thank O. Gabay for the graphical work and B. Knisbacher and the Levanon laboratory members for fruitful discussions. The authors also thank J. Rosenthal and J-B. Li for critical reading of the manuscript. This work was supported by the European Research Council (grant 311257), the Israel Science Foundation (1380/14) and the Minerva Stiftung ARCHES award from the Federal German Ministry for Education and Research (BMBF) to E.Y.L. E.E. was supported by the Israel Science Foundation (2673/17) and the United States-Israel Binational Science Foundation (094/2013).

Reviewer information

Nature Reviews Genetics thanks L. Keegan, M. Öhman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Both authors contributed to all aspects of this manuscript.

Correspondence to Eli Eisenberg or Erez Y. Levanon.

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Glossary

Non-coding RNAs

RNA transcripts that are not translated into proteins but may have a regulatory function.

MicroRNAs

Short non-coding RNAs that regulate gene expression post-transcriptionally, mainly by binding to the 3′ untranslated region of mRNA.

Circular RNAs

RNA molecules that form a covalently closed continuous loop. They were found only recently, and the function of most of them is not known.

RNA modifications

Changes to the chemical composition of RNA molecules that have the potential to alter their function or stability.

Editome

The entire set of RNA editing events in a genome.

Non-synonymous substitutions

Replacement of one base by another within a coding region of a gene, which results in an amino acid change in the protein sequence.

Low-coverage

Arises when the number of reads that include a given nucleotide is insufficient to provide reliable variant calling at that position in the reconstructed sequence.

Ultra-deep sequencing

The application of massively parallel sequencing methods to a small set of targets, yielding much higher read coverage than that obtained from standard whole-transcriptome RNA sequencing data.

Purifying selection

Selective removal of deleterious alleles from the general population.

Retro-elements

Mobile elements that move around the genome through transcription into RNA followed by reverse transcription.

Mobile elements

DNA fragments that can move around within the genome. Most of the mammalian genome is composed of sequences derived from mobile genetic elements.

Exonization

Recruitment of a new exon from non-protein-coding intronic DNA, mostly from mobile elements.

Synonymous substitutions

Replacement of one base by another within a coding region of a gene, which does not result in an amino acid change in the protein sequence.

Exapted

A trait, a gene or a cellular process that has changed function during evolution.

Adaptation

The evolutionary process by which the genetic information carried by a population of organisms is adjusted to improve their fitness to the environment.

Acclimation

The process by which an individual organism adjusts to a short-term change in its environment (as opposed to genomic changes on evolutionary timescales, called adaptation).

Somatic mutation

An alteration in DNA that occurs after conception. Somatic mutations are not shared by all cells of the body.

Passenger mutations

Mutations that are caused by genomic instability, which is common in cancer cells, but do not promote malignancy.

Driver mutations

Mutations that provide cancer cells with a selective advantage and promote malignancy.

Nanopore sequencing platforms

Emerging sequencing methods by which a single molecule of DNA or RNA can be sequenced without the need for PCR amplification.

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Eisenberg, E., Levanon, E.Y. A-to-I RNA editing — immune protector and transcriptome diversifier. Nat Rev Genet 19, 473–490 (2018) doi:10.1038/s41576-018-0006-1

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