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  • Review Article
  • Published:

The many roles of an RNA editor

Nature Reviews Genetics volume 2, pages 869–878 (2001)Cite this article

Key Points

  • RNA editing describes the changes that take place in the RNA sequence after transcription is completed. Examples include modification of cytosine to uracil or of adenine to isoleucine by deamination, or insertion and/or deletion of particular bases.

  • In the apolipoproteinB (APOB) mRNA, the deamination of a cytosine to a uracil generates a stop codon, so leading to the synthesis of a shorter protein isoform. The minimum protein requirements for editing APOB mRNA are the deaminase enzyme APOBEC1 and the auxiliary factor ACF.

  • Sequence motifs in APOBEC1 and ACF are reminiscent of the domains that are present in the ADAR (adenosine deaminases that act on RNA) family of enzymes, which have a catalytic deaminase domain and an arginine/glycine-enriched domain. In addition, ACF has a putative double-stranded RNA-binding domain that is present in ADAR proteins.

  • Three proteins that are homologous to APOBEC1 (AID, APOBEC2 and phorbolin1) have been isolated; however, these are unable to edit APOB mRNA and it is uncertain whether they are RNA-editing enzymes.

  • There are three, highly homologous, mammalian ADAR enzymes. ADAR1 and ADAR2 can convert specific adenosines to inosines in pre-mRNA. Most transcripts that are edited are specific to the central nervous system.

  • Even though ADAR1 and ADAR2 have overlapping specificities in vitro, transgenic experiments in mice have shown that the enzymes cannot compensate for one another and that each is required to edit specific transcripts.

    In some instances, there seems to be a link between RNA editing and splicing, whereby editing is required for efficient splicing.

  • ADARs edit transcripts in the 5′ and 3′ untranslated regions, as well as in exonic and intronic regions. This raises the possibility that RNA editing has other roles in the cell besides generating codon diversity. For example, it might also function in RNA transport or stability.

  • There is a link in mice between the inability to edit the glutamine/arginine site in the glutamate-gated ion channel receptor B transcript and epilepsy. Also hyper-editing of viral transcripts has been associated with certain fatal diseases.

Abstract

The availability of complete genome sequences has made it clear that gene number is not the sole determinant of the complexity of the proteome. Additional complexity that is not readily detected by genome analysis is present in the number and types of RNA transcript that can be derived from each locus. Although alternative splicing is a well-recognized method of generating diversity, the more subtle mechanism of RNA editing is less familiar.

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Figure 1: The processing of RNA in a cell.
Figure 2: Recognition of the edited nucleotide by the editing enzymes.
Figure 3: Schematic diagram of human ADAR, APOBEC1 and ACF.
Figure 4: Editing of adenosine bases.

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Acknowledgements

We are grateful to N. Gray and D. Scadden for their helpful comments and to S. Bruce for drawing the original figures. In addition, we are grateful to B. Bass, D. Morse and P. Seeburg for sharing unpublished work, and to W. Keller and R. Reenan for their many discussions. We apologize to colleagues whose work could not be cited due to space constraints. Work in the authors' laboratory is supported by the MRC and a grant from the British Heart Foundation.

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Authors and Affiliations

  1. MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK

    Liam P. Keegan, Angela Gallo & Mary A. O'Connell

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  1. Liam P. Keegan
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  2. Angela Gallo
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  3. Mary A. O'Connell
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Corresponding author

Correspondence to Mary A. O'Connell.

Related links

Related links

DATABASE LINKS

Locuslink 

ACF

ADAR1

ADAR2

ADAR3

AID

APOB

APOBEC1

APOBEC2

GRY-RBP

NF1

PTPN6 

OMIM 

acute myeloid leukaemia

Alzheimer disease

Huntingdon disease

hyper-immunoglobulin M

measles inclusion body encephalitis

schizophrenia

subacute sclerosing panencephalitis

SWISS-PROT

5-HT2C

dsRBD

eIF4G

KSRP

Glossary

CAPPING

The process by which eukaryotic mRNA is modified by the addition of an m7G(5′)ppp(5′)N structure at the 5′ terminus. Capping is essential for several important steps of gene expression: for example, mRNA stabilization, splicing, mRNA export from the nucleus and initiation of translation.

KINETOPLAST

An intracellular DNA-containing structure that is a modified mitochondrion with an associated centriole-like organelle (kinetosome), which is characteristic of the class that includes trypanosomes.

PLASMA

A blood component that is composed of 90% water and transports blood cells, nutrients, waste products, salts, antibodies, clotting proteins, hormones and proteins that help maintain the fluid balance of the body.

DEAMINATION

The removal of an amino group from a nucleoside, thereby generating another nucleoside with different base-pairing properties.

TRIGLYCERIDE

Fat compound in the body and in most food that is composed of a glycerol molecule with three fatty-acid chains attached through their hydroxyl groups.

LOW-DENSITY LIPOPROTEIN

Insoluble lipid that is transported in the blood and is associated with cholesterol, phospholipids and protein to form a lipoprotein complex. Low-density lipoprotein (so defined by the type and ratio of protein and fats that it contains) is the main cholesterol carrier in the blood.

CHYLOMICRON

Large lipoprotein complex formed in the intestine that transports fats from the intestine to the liver and to adipose tissue.

MOORING SEQUENCE

An 11-nucleotide motif, which is located 3′ of the cytidine that is edited in APOB mRNA. Both APOBEC1 and ACF are thought to bind to this motif.

IMMUNOGLOBULIN CLASS SWITCHING

A DNA recombination event that only occurs at the immunoglobulin (Ig) heavy chain locus in B cells and is the process by which IgG, IgA and IgE antibodies can be produced instead of IgM.

SOMATIC HYPERMUTATION

The process by which point mutations are introduced into the V(D)J exon of immunoglobulin genes in B cells to create diversity.

PSORIASIS

A chronic skin disease that is characterized by scaling and inflammation. The exact cause is unknown but it is probably a disorder of the immune system.

HYDROLYTIC DEAMINATION

The process in which an amino group is removed from an adenosine residue and is replaced with the oxygen from water to produce inosine and ammonia.

METALLOENZYME

A group of proteins that contain metal-binding sites.

DNA METHYLTRANSFERASE

Enzyme that catalyses the addition of a methyl group to adenine or to cytosine.

INTERFERON

One of a family of proteins that occurs naturally in the body as part of its defence mechanism. It can be subdivided into three distinct types: α, β and γ.

Z-DNA

A left-handed form of DNA that can occur at stretches of alternating G and C bases. So named because of its zig-zag backbone.

PSEUDOURIDINE

One of the most abundant modified nucleosides found in RNA; it is the result of a post-transcriptional isomerization of uridine.

PREFRONTAL CORTEX

Region of the brain that is important for mood states and might harbour abnormalities in patients with unipolar and bipolar depression.

STRIATUM

Region of the brain that receives excitatory input from the cortex, thalamus and midbrain. It has a pivotal role in modulating motor activity and higher cognitive function.

POLYOMA VIRUS

DNA virus that causes subclinical infections early in childhood. It leads to viral latency within the kidney but reactivation occurs in transplant recipients as a result of immunosuppressive therapy.

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Keegan, L., Gallo, A. & O'Connell, M. The many roles of an RNA editor. Nat Rev Genet 2, 869–878 (2001). https://doi.org/10.1038/35098584

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