From the Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106
RNA editing is the changing of a nucleotide
sequence at one or more positions within an RNA transcript. Hence,
editing leads to the formation of transcripts, the sequence of which
differs from that found in the genome. RNA editing was initially
described in the 1980s in a unicellular protozoan (1) and soon
thereafter in the mouse (2, 3) and also in a viral pathogen that
affects humans (4). The frame-shifted cytochrome oxidase
coxII gene transcript of trypanosome mitochondria provided
the first example of RNA editing when it was found to contain four
inserted uridines that were not encoded by the genomic DNA (1).
Subsequently, editing by nucleotide substitution was described for the
apolipoprotein B (apoB) transcript in mouse intestine (2) and the
glutamate-gated ion channel
(GluR-B)1 transcript in mouse
brain (3). ApoB mRNA possesses a UAA translational stop codon, at a
position where the genomic DNA specifies a CAA glutamine codon (2). The
edited GluR-B mRNA possesses a CIG arginine codon (I is recognized
as G by decoding ribosomes), whereas unedited mRNA possesses the
genome-encoded CAG glutamine codon at the same position (3). Finally,
measles virus RNA isolated from brains of persistently infected
subacute sclerosing panencephalitis patients were shown to possess
multiple differences from the sequence of the viral RNA genome,
differences that correspond to A-to-G and U-to-C substitution mutations
(4). RNA editing now is known to occur in a wide range of eukaryotic
organisms and their viruses (5-7), and more examples are likely to be
uncovered in the future.
What are the biochemical mechanisms responsible for RNA editing? The
two minireviews in this issue focus on the genetic and biochemical
aspects of nucleotide substitution RNA editing by deamination, either
A-to-I (8) or C-to-U (9). The substrates and enzymes responsible for
these editing processes are reviewed, along with the functional roles
that representative editing events play in cellular processes. A third
minireview that focused on 2'-O-methyl ribose nucleotide
modification, uridine to pseudouridine conversion, and RNA-guided
editing events mediated by small nucleolar RNA cofactor guides and
associated proteins was published recently (10).
In the first minireview, Stefan Maas, Alexander Rich, and Kazuko
Nishikura in their article entitled "A-to-I Editing: Recent News and
Residual Mysteries" review new developments in the biochemistry and
biology of editing by C-6 adenosine deamination (8). Recent advances in
understanding the physiologic significance of individual members of the
multigene family of adenosine
deaminases that act on RNA (ADAR)
enzymes, and the biochemical activities associated with the
double-stranded RNA binding, Z-DNA binding, and catalytic domains of
the ADAR deaminases are described. The enzymatic deamination of
adenosine in pre-mRNAs and other structured RNAs is evaluated in
the context of the components of the RNA editing machinery that carry
out deamination editing of the A-to-I variety. The expression of ADAR
enzymes is a complex process. This is illustrated by the
ADAR1 gene, where alternative promoters including one
inducible by interferons together with alternative splicing give rise
to different protein isoforms. Information derived from the study of
gene disruptions of ADARs has led to important insights into the roles
of A-to-I editing. Pre-mRNA substrates encoding glutamate receptor
and serotonin 2C receptor proteins provide two examples whereby A-to-I
editing gives rise to amino acid substitutions, changes that alter the
sequences and hence activities of the encoded proteins.
The second minireview of the series by Valerie Blanc and Nicholas O. Davidson entitled "C-to-U RNA Editing: Mechanisms Leading to Genetic
Diversity," summarizes progress in understanding the biochemical
mechanisms and substrate targets for C-to-U RNA editing in mammals
(9). Like A-to-I editing, C-to-U RNA editing is catalyzed by a
deaminase that acts on the target RNA substrate. However, important
differences exist between the biochemistry of C-to-U and A-to-I
editing. The known C-to-U editing events involve a single-strand
substrate, occur on spliced RNAs in the nucleus, and are mediated by a
multicomponent complex that includes one or more associated protein
complementation factors in addition to the catalytic deaminase
(apobec-1). ApoB and neurofibromatosis type 1 (NF1) mRNA substrates
provide two examples whereby C-to-U editing gives rise to translational
stop codons that shorten the respective open reading frames and hence
coding capacity of the mRNAs.
Altering the information transfer process at the post-transcriptional
level of gene expression by nucleotide substitution editing through A
or C deamination mechanisms represents an important strategy for
amplifying genetic diversity and modifying the functions of products
encoded by an organism's genome (5-7). Some of the established and
potential roles that A-to-I and C-to-U RNA editing plays, or may play,
in biologic processes are summarized in Fig. 1. These include effects on mRNA
translation, pre-mRNA splicing, RNA degradation, RNA replication,
and RNA structure that result from A-to-I or C-to-U deaminations
(5-9). Site-specific editing may change the coding potential of
mRNA transcripts, leading to proteins with altered function due to
amino acid substitutions following A-to-I editing, as exemplified by
GluR-B and serotonin 2C receptor proteins. Introduction or removal of
translation termination codons may also occur, as exemplified by apoB
and NF1 mRNAs where C-to-U editing generates UAA and UGA
translation stop codons, respectively, and hepatitis delta virus RNA
where A-to-I editing converts an amber UAG stop to an UIC tryptophan
codon. ADAR2 edits its own transcript to create an alternative splice
acceptor site. Additionally, a novel ribonuclease selective for
inosine-containing RNAs has been identified, which creates the
possibility that A-to-I edited transcripts may be degraded
preferentially relative to the unedited transcripts. For some viral
RNAs, modifications characteristic of adenosine deamination are seen
which, following RNA replication, would be expected under certain
conditions to lead to changes in the encapsidated viral genome
sequence. Finally, sequence changes resulting from editing may
subsequently affect RNA structure and hence function, including altered
binding of RNA by proteins (Fig. 1).
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Fig. 1.
Established and potential roles of RNA
editing by deamination. Edited RNA transcripts (A-to-I; C-to-U)
possess sequences different from their unedited transcript counterparts
and hence may display functional activities different from that shown
by the unedited transcripts. Editing may alter processes including
mRNA translation by changing codons and hence coding potential;
editing may alter pre-mRNA splicing patterns by changing splice
site recognition sequences; editing may affect RNA degradation by
modifying RNA sequences involved in nuclease recognition; editing may
affect viral RNA genome stability by changing template and hence
product sequences during RNA replication; and editing potentially may
affect RNA structure-dependent activities that entail
binding of RNA by proteins.
Much progress has been made in our understanding of the mechanisms and
roles of RNA editing. Identification of additional mRNA substrates
that undergo editing by deamination and establishing the functional
roles that editing events play in biologic processes, together with
further definition of the biochemical and regulatory mechanisms of
A-to-I and C-to-U editing, present some of the immediate challenges and
opportunities in the RNA editing field.
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FOOTNOTES |
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* These minireviews will be reprinted in the 2003 Minireview Compendium, which will be available in January 2004.
To whom correspondence should be addressed. Tel.: 805-893-3097;
Fax: 805-893-5780; E-mail: samuel@lifesci.ucsb.edu.
Published, JBC Papers in Press, November 20, 2002, DOI 10.1074/jbc.R200032200
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ABBREVIATIONS |
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The abbreviations used are: GluR, glutamate receptor; ADAR, adenosine deaminase acting on RNA; NF1, neurofibromatosis type 1.
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REFERENCES |
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