From the Department of Biology, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139 and
¶ The Wistar Institute, Philadelphia, Pennsylvania 19104
Adenosine to inosine modification in
pre-mRNA, with inosine acting as guanosine during translation, was
the most recent type of RNA editing to be discovered (1). At present,
it appears to be the most widespread type of nuclear pre-mRNA
editing in higher eukaryotes (6, 14, 25). Adenosine deaminases acting on RNA (ADARs),1 the enzymes
responsible for conversion of A-to-I in double-stranded (ds) RNA, were
first noticed as cellular RNA unwinding activity (2, 3), as they lead
to destabilization of RNA duplexes by introducing I·U mismatches.
Since the initial cloning of the first RNA-specific adenosine
deaminase, ADAR1 (4, 5), a family of A-to-I editing enzymes (ADAR1-3)
has emerged (Fig. 1) (6-10). Both ADAR1
and ADAR2 are detected in many tissues, whereas ADAR3 is expressed only
in restricted regions of the brain (4, 5, 7-10). Members of the ADAR
gene family share common structural features such as two or three
repeats of a dsRNA binding motif and a separate deaminase or catalytic
domain (4, 5). Certain structural features are unique to particular
ADAR members. For instance, ADAR1 contains two Z-DNA binding motifs
(11), whereas ADAR3 includes an arginine-rich single-stranded RNA
binding domain at the N terminus (9, 10) (Fig. 1). In vitro
RNA editing studies have revealed a significant difference in site
selectivity displayed by ADAR1 and ADAR2 (7, 8), whereas no RNA editing activity has been demonstrated yet for ADAR3 (9, 10). Orthologues of
the mammalian ADARs have also been characterized and cloned from fruit
fly (12) and worms (6) (Fig. 1), and related genes have been identified
in fish genomes (13). Subsequently, the subfamily of
tRNA-specific A-to-I editing enzymes (ADAT1-3) was uncovered based on
their sequence homologies to ADARs. ADAT3 is an adenosine deaminase in
yeast shown to form an enzymatically active heterodimer with ADAT2
(14). ADAT1 and ADAT2 are conserved from yeast to humans (15), and it
is believed that an ADAT1-like adenosine deaminase is the ancestor of
the current A-to-I editing enzymes (14).
A partially double-stranded RNA structure involving exonic and
intronic sequences seems essential for editing to take place (16-18).
By far, most of the genes found to undergo A-to-I RNA editing in
mammals, Drosophila melanogaster, Caenorhabditis elegans, and squid, are expressed in the nervous system. Prominent examples are
transcripts of the mammalian glutamate receptors (GluRs) and the
serotonin receptor subunit 2C (5-HT2CR), where deamination of exonic adenosines leads to single amino acid changes in the resulting proteins often with profound consequences for receptor function (see Fig. 2). A-to-I editing was
also found to occur in non-coding regions of pre-mRNAs (17, 19),
most notably in the transcripts of the editing enzyme ADAR2 (19). By
editing its own transcripts, an alternative splice acceptor site is
created in intron 1, leading to alternative splicing resulting in a
nonfunctional protein (19). Interestingly, the only ADAR-like gene in
Drosophila, DADAR, which is most closely
related to the mammalian ADAR2 protein, is also self-edited but within
the coding region (12).
INTRODUCTION
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Fig. 1.
Characterized ADARs. Z ,
Z
, DNA binding domains; R-rich, domain
rich in arginines; dsRBD, double-stranded RNA binding
domain; deaminase, adenosine deaminase domain; Tad2/Tad3p
heterodimers edit the wobble position in several tRNAs.
ADAR Substrates
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Fig. 2.
Prominent examples of mammalian A-to-I
editing.
A-to-I RNA editing of the antigenome RNA of hepatitis delta virus, which replaces a translational stop signal with a tryptophan codon (UAG to UGG) (20) is an obligatory step in the hepatitis delta virus life cycle. In addition, an intronic branch site adenosine of SH-PTP1 tyrosine phosphatase has been proposed to be edited by ADAR (21). No examples have yet been identified of A-to-I editing creating a translational start codon (ATA to ATG) or changing a consensus polyadenylation signal (AAUAAA). However, such discoveries are likely.
In contrast to its exquisite selectivity for adenosine residues deaminated in a natural RNA substrate with a characteristic hairpin structure including loops and bulges, ADARs almost randomly modify many adenosines (~50%) within a long completely complementary dsRNA. One source of such extended dsRNA molecules is viral RNAs that are synthesized during replication and also transcription of viral genomes. These viruses, such as measles, seem to encounter ADARs and under certain circumstances are converted to hypermodified dsRNAs with many I·U mismatched base pairs, denoted I-dsRNAs (6, 22).
The physiological importance of A-to-I RNA editing has been confirmed
by analysis of ADAR null mutation phenotypes. For instance, ADAR2/
mice died young after repeated
episodes of epileptic seizures caused by underediting of GluR-B RNA at
the Q/R site, which controls Ca2+ permeability of the
resulting ion channel (23). Lethal phenotypes including
dyserythropoietic defects were observed in chimeric mouse embryos
derived from ADAR1+/
embryonic stem cells.
However, the possibility that antisense transcripts derived from the
ADAR1 targeted allele may contribute to the observed
phenotypes has not been ruled out (24). The genetic inactivation of
DADAR in Drosophila resulted in flies with
extreme behavioral deficits and neurological symptoms such as
paralysis, locomotor uncoordination, and tremors, which increased in
severity with age (25). The observed phenotype is likely to be the
result of the total lack of A-to-I RNA editing in the brains of the
mutant flies (25). In light of these findings it can be speculated that
dysfunction of A-to-I RNA editing in humans could be cause for or
contribute to certain pathophysiological processes and diseases.
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A-to-I RNA Editing of Repetitive Sequences within Introns and 3'-UTRs |
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The measured amount of inosine, especially in the brain, is substantial and suggests that many genes undergo A-to-I editing (26). However, since the initial discovery of A-to-I RNA editing (1), only a few edited genes have been identified from discrepancies between the mRNA (cDNA) and genomic sequences, and their discovery was entirely serendipitous. A recently devised method for the enrichment and cloning of inosine-containing RNAs provides the first comprehensive search tool and has lead to the isolation of new edited RNA sequences; 10 from C. elegans and 19 from human brain (27). They include transcripts from diverse genes such as tankyrase, NADH-ubiquinone oxidoreductase, and a snoRNA precursor (27). All of the identified RNAs have A-to-I conversions in non-coding regions, mainly in 3'-UTR and intronic sequences, often involving repetitive elements such as Alu and LINE1 repeats (27). Potentially, the modifications in 3'-UTR secondary structures could alter the stability, transport, or translation of the mRNA, and intronic editing might influence the kinetics or efficiency of splicing (Fig. 2).
Because no novel or known genes with editing sites in coding regions were isolated during the unbiased screening (27), it might be that the editing events that were discovered previously within the coding regions represent exceptional cases where, due to the beneficial function of the edited gene variant, positive selection has led to an increase in editing rates. It will be interesting to see if exhaustive screening of the enriched RNA pools will eventually lead to an accurate estimate of the total number of edited genes in the mammalian genome and the ratio of coding to non-coding editing sites.
However, two dozen or so newly identified genes do not explain the
discrepancy between significant amounts of inosine detectable within
the poly(A) fraction of cellular RNA on one hand and the paucity of
newly identified targets on the other. What could explain this seeming
contradiction? One possibility is that there are a small number of
genes that get edited extensively, contributing most of the measurable
inosine. Such a mode of modification by ADARs, termed hyperediting, has
previously been reported for the host-induced editing of viral RNAs
(6). Indeed, some of the substrates in C. elegans and human
are modified at multiple positions (27). At the same time, the observed
amount of inosine in mRNA (up to 1 inosine in every 17,000 nucleotides (26)) could also be explained if many genes are edited at
few positions but with low efficiency. This would make it much more
difficult to identify individual editing events, because only a small
fraction of the gene's transcripts carry the modification. Also, it is
possible that the RNA editing machinery continuously probes nascent
transcripts for new editing sites. In light of the few constraints on
non-coding sequences (i.e. intronic, 5'-UTR, and 3'-UTR),
novel, editable RNA structures could continue to appear at a
significant rate within the pool of primary transcripts. Because such
probing is a non-directional and initially low rate phenomenon, it
would be difficult to detect these editing events and to distinguish them from reverse transcription or sequencing errors. One can imagine a
scenario where opportunistic editing of newly formed RNA structures
generates a constant "inosine background" that could account for
most of the inosine measured. This is supported by the fact that the
abundance of repetitive sequences in the mammalian genomes, some still
active mobile elements, leads to a high number of inverted repeats
embedded within expressed sequences. The presence of repetitive
elements in most of the newly identified editing substrates certainly
supports the latter scenario. It is tempting to speculate that ADARs
might be involved in the regulation of transposons and repetitive
elements or possibly in the phenomena of gene imprinting and X
chromosome inactivation (Fig. 3).
Repetitive sequences and transcription of sense and antisense strand
RNA, both with the potential to form dsRNA, have been proposed to play a critical role in these epigenetic modification processes (28).
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More Recoded Transcripts and Consequences |
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Several new A-to-I RNA editing sites occurring within the coding
regions of neurotransmitter receptors and channels have been reported
recently. In D. melanogaster, transcripts for the putative nicotinic acetylcholine receptor D6 were found to be edited at several positions within the ligand binding region of the receptor channel (29). This finding adds another neurotransmitter receptor to
the growing list of genes targeted for A-to-I editing that reside in
the nervous system. Furthermore, a novel case of invertebrate A-to-I
editing characterized in squid also involved a gene important for
neurotransmission: the delayed rectifier K+ channel
(SqKv1.1A) (30). Thirteen editing sites have been identified, which are
all positioned in membrane-spanning segments with influence on the
channel's gating behavior. In addition, one editing site located in a
domain important for subunit assembly was shown to regulate
tetramerization of the subunits (30). Curiously, the fact that eight
valine residues are introduced by editing is reminiscent of the cluster
of adaptive mutations occurring in certain fish genes to maintain their
function at low temperature, suggesting a possible
temperature-dependent regulation of editing (30, 31).
An important function for channel subunit trafficking and assembly has
recently been traced to the same editing position in GluR-B, which
dominantly regulates channel gating (32) and also is important for
efficient further processing of its pre-mRNA (23). The edited
GluR-B subunits (harboring an arginine at the Q/R site) are retained
within the endoplasmic reticulum until incorporation of the protein
into heteromeric receptors (32). Thus, the Q/R site of GluR-B is the
molecular determinant for a set of critical receptor functions, and all
of them rely on the quantitative recoding of the glutamine codon by RNA
editing (31, 32).
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Deregulation of A-to-I RNA Editing |
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Could local or systemic A-to-I editing activity be the cause of phenotypes that correspond to known diseases in humans, in particular, with respect to brain disorders and neurodegenerative processes? Editing of 5-HT2C receptor pre-mRNA at a total of five sites leads to replacement of three amino acid residues in the second intracellular domain, resulting in dramatic alterations in G-protein coupling functions of the receptor (16). Among all RNA editing isoforms detected, those carrying Gly at position 158 displayed the most dramatically decreased G-protein coupling activities (33). Interestingly, substantial alterations in the 5-HT2C receptor RNA editing levels and concomitant increase in the expression of the receptor isoform carrying Gly at position 158 were observed in the prefrontal cortex of suicide victims (34). The measured changes in the expression pattern of the receptor isoforms are anticipated to have resulted in dampening of the overall efficacy of serotonergic neurotransmission in these depressed individuals (34). Interestingly, the treatment of mice with an antidepressant ProzacTM (serotonin re-uptake inhibitor) induced changes in editing levels that were converse to those observed in suicide victims (34). These preliminary results, together with two related reports (35, 36), raise the possibility that changes in RNA editing of the 5-HT2CR may be involved in the etiology of neuropsychiatric disorders and also that dynamic changes in editing levels could be induced by various psychoactive drugs and antidepressants. Due to the high variance in 5-HT2CR editing within different cell types of the brain and our present ignorance about how RNA editing is regulated, larger data sets will be needed to assess the significance of these findings for those disease states and to unravel the causal relationships between changes in serotonin levels and alteration in editing (31, 34).
With respect to the editing of glutamate receptors in the central
nervous system, mounting evidence points to a link between abnormal
editing levels and seizure vulnerability. Epileptic seizures are the
major phenotypic features of transgenic mice with underediting at the
GluR-B Q/R site, mainly due to the increased macroscopic AMPA-R
conductance in these mice (23, 37, 38). Also, when eliminating Q/R site
editing in the GluR-6 kainate receptor subunit, the mutant mice exhibit
an increased susceptibility to kainate-induced seizures (39).
Underediting of the GluR-B Q/R site might, among other reasons, also be
an explanation for the occurrence of epileptic seizures in patients
with glioblastomas (malignant tumors of glia cells) (40). This is
suggested from findings that in these tumors the RNA editing activity
of ADAR2, the enzyme crucial for GluR-B Q/R site editing (23), is
significantly depressed (40). Tumor-intrinsic Q/R site editing was
decreased to levels comparable with those measured in the mouse models.
As in the other cases described, it will be important to determine
whether the observed changes in RNA editing patterns are consequences
of the disease state or are involved in driving disease progression. In
either case, the clinical symptoms of depression (5-HT2CR)
or epilepsy (GluR) might be treated more effectively if account is
taken of the concomitant deregulation in RNA editing.
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Determinants for A-to-I RNA Editing Efficacy |
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What are the determinants that could cause a significant change in the rate of editing at a specific site? Currently, we can neither extract that information from known ADAR substrates nor predict whether a given RNA sequence will be edited in vivo. Apart from the requirement for double-stranded regions and certain 5' and 3' neighbor preferences that allow for the assessment of editing probability in vitro (6), additional features of the substrates and additional protein factors appear to be involved in vivo. A major consideration for what happens in vivo will be how accessible the RNAs actually are for binding and modification by these enzymes.
Because of the involvement of intronic sequences in the dsRNA
structures essential for editing of 5-HT2CR and GluR
pre-mRNA, A-to-I RNA editing must occur before or simultaneously
with splicing. Therefore, it is likely that RNA editing and splicing
machineries interact with each other (Fig.
4). In the brains of
ADAR2/
mice the almost complete absence of GluR-B RNA
editing at the Q/R site due to the total loss of the editing enzyme
ADAR2 indeed changed the kinetics of splicing (10-fold reduction) (23),
confirming the close relationship between the processes of RNA editing
and splicing. In fact, the minute amounts of edited GluR-B primary transcripts undergo preferential splicing as judged from the level of
editing measured in mature GluR-B mRNA (40% Arg compared
with 10% in GluR-B pre-mRNA (23)). Preferential splicing of edited transcripts has also been observed in the case of ADAR2 self-editing (40).
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A growing number of snoRNAs are found that guide the methylation and uridylation of rRNAs, tRNAs, snRNAs, and probably mRNAs through the formation of a short RNA duplex with their target sequences (reviewed in Ref. 41). One such mammalian snoRNA, specifically expressed in the brain and paternally imprinted, harbors a guide sequence specific for 5-HT2CR mRNA (42). Intriguingly, it is predicted to guide the 2'O-methylation of the adenosine residue, which also undergoes A-to-I editing (C site). The modification is expected to interfere with the ADAR deamination reaction (Fig. 4). Again, the relative localization of the methylation and editing machineries may be the most important factor in determining the kind and rate of modifications introduced.
The stability of a dsRNA structure, especially one with many mismatched
base pairs and bulges, may be sensitive to subtle change of body
temperature (31); a feature of particular importance for poikilotherms.
Opening of the dsRNA structure involved in A-to-I RNA editing, possibly
regulated by various dsRNA helicases and annealing activities, appears
to be another critical step (Fig. 4). Mutation in RNA helicase A, a
specific ATP-dependent dsRNA helicase, blocks resolution of
the dsRNA structure and results in the occurrence of a "splicing
catastrophe" or aberrant splicing and skipping of exons of the
Drosophila para-Na+ channel transcripts at the
region surrounding the editing sites (43). This indicates that the
overall editing efficiency of a given substrate RNA may significantly
change depending on the stability of the dsRNA structure and/or its
splicing rate (43). Furthermore, it has been reported recently that
both ADAR1 and ADAR2 proteins are complexed with large nuclear
ribonucleoprotein particles that constitute all known factors required
for pre-mRNA splicing (44). This suggests an interesting
possibility that certain physiological conditions (e.g.
fever or hypothermia) or pharmacotherapies may affect directly or
indirectly the availability and abundance of RNA helicase A or various
splicing factors as well as ADAR expression levels, which all in turn
regulate RNA editing levels (33, 43) (Fig. 4).
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ADAR1 Functions in Processes Other Than Site-selective Pre-mRNA Editing |
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A number of unique structural and functional features set ADAR1 apart from the other known ADAR gene family members (Fig. 1). Although in vitro ADAR1 has been shown to be capable of carrying out editing of certain sites such as the A and B sites in 5-HT2CR transcripts (10, 45) and the intronic hotspot1 in GluR-B (7, 23), its involvement in vivo in site-selective editing of nuclear pre-mRNA has not yet been demonstrated. Its unique domain architecture, expression, and localization indicate that ADAR1 might in fact have in vivo functions other than nuclear pre-mRNA editing. Two major ADAR1 variants, differing in the lengths of their N-terminal sequence, are expressed due to the use of different promoters. The interferon-inducible, full-length ADAR1 150-kDa protein is present in both the cytoplasm and nucleus, whereas the constitutively expressed 110-kDa isoform is exclusively nuclear (46) (Fig. 3). A role for the 150-kDa ADAR1 in the cellular, interferon-mediated antiviral response has been postulated (6, 46). The 150-kDa ADAR1 includes a unique N-terminal domain that has been shown to bind DNA in the Z-conformation with high affinity. One supposition has been that Z-DNA binding helps to localize ADAR1 to actively transcribed target genes (11), and Z-binding proteins have recently been implicated in the modulation of chromatin remodeling (47). Within the same N-terminal region of the 150-kDa ADAR1 protein a nuclear export signal was found, which leads to nucleocytoplasmic shuttling of the enzyme (48).
Any RNA that is at least partially double-stranded represents a
potential substrate for A-to-I editing. This raises the question of
whether other cellular processes that rely on double-stranded RNA
molecules as functional entities, such as RNAi, will be influenced by
A-to-I RNA editing (Fig. 3). RNAi is a post-transcriptional process
whereby dsRNA induces the homology-dependent degradation of
cognate mRNA in the cytoplasm. RNAi may be involved in other processes such as chromatin remodeling in the nucleus. For the RNAi
mechanism operating in the cytoplasm, the most significant member of
the ADAR gene family is the 150-kDa form of ADAR1. The potency of the
trigger dsRNAs mediating RNAi has been reported to be significantly
reduced following A-to-I editing in vitro by ADAR proteins
(49). Thus it is possible that ADAR1 may interact with
precursors of the recently identified class of short RNAs such as
micro-RNAs and small transient RNAs and affect their synthesis (Fig.
3).
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Cellular Activities Specific for Inosine-containing RNAs |
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The studies described above may indicate the presence of a
mechanism to eliminate or deal with dsRNA, either viral or cellular, after hypermodification by ADARs. Several cellular activities that
specifically act on inosine-containing RNA (I-RNA or I-dsRNA) have been
identified (Fig. 3). A cytoplasmic ribonuclease activity that
specifically cleaves I-dsRNA (I-RNase) has been reported recently.
Cleavage occurs at specific sites with dsRNA consisting of alternate
I·U and U·I base pairs, presumably introduced by p150 ADAR1 (50).
In addition, a nuclear-localized protein p54nrb capable
of binding to hypermodified I-RNAs has also been reported (22). The
biological function of p54nrb, which forms a protein complex
with two other proteins, PSF (splicing factor) and matrix 3 (nuclear
matrix protein), is currently not understood (22). Taken together,
these cellular activities specific for inosine-containing RNAs
represent the "smoking gun" of frequent encounters between ADARs
and endogenous or viral dsRNA and provide evidence for the existence of
cellular mechanism(s) to process hypermodified RNA molecules.
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FOOTNOTES |
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* This minireview will be reprinted in the 2003 Minireview Compendium, which will be available in January, 2004. This work was supported in part by grants from the National Institutes of Health (to A. R. and K. N.), the National Science Foundation (to A. R.), the Doris Duke Charitable Foundation (to K. N.), the Israel-United States Binational Science Foundation (to K. N.), the March of Dimes (to K. N.), and the Anna Fuller Fund (to S. M.). This is the first article of two in the "RNA Editing Minireview Series."
§ To whom correspondence may be addressed: Dept. of Biology, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139. Tel.: 617-258-9299; Fax: 617-253-8699; E-mail: cbeckman@mit.edu.
To whom correspondence may be addressed: The Wistar Institute,
3601 Spruce St., Philadelphia, PA 19104. Tel.: 215-898-3828; Fax:
215-898-3911; E-mail: kazuko@wistar.upenn.edu.
Published, JBC Papers in Press, November 20, 2002, DOI 10.1074/jbc.R200025200
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ABBREVIATIONS |
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The abbreviations used are:
ADAR, adenosine
deaminase acting on RNA;
GluR, glutamate receptor;
AMPA, -amino-3-hydroxy-5-methylisoxazole-4-propionic acid;
5-HT, 5-hydroxytryptamine or serotonin;
5-HT2CR, serotonin
receptor subtype 2C;
dsRNA, double-stranded RNA;
ADAT, adenosine
deaminase acting on tRNA;
snoRNA, small nucleolar RNA;
RNAi, RNA
interference.
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