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GREAT EXPERIMENTS
The discovery of RNA-guided RNA modification
Tamás Kiss
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Introduction
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In addition to the four classical
ribonucleotides, adenosine, guanosine, cytidine and uridine, several
cellular RNAs also contain a number of structurally diverse
ribonucleotides. These so called modified ribonucleotides are
synthesized post-transcriptionally by covalent modification of the
classical ribonucleotides (see tRNA contains modified bases and
Small RNAs are required for rRNA processing).
During the last 40 years, almost a hundred different modified
nucleotides have been identified in transfer RNAs (tRNAs), ribosomal
RNAs (rRNAs) and small nuclear RNAs (snRNAs). In tRNAs, modified
nucleotides are important determinants of the specificity and
efficiency of aminoacylation and codon recognition (for review see 1395)
(and see Modified bases affect anticodon-codon pairing).
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Background
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Figure 1
In 2′-O-methylated nucleotides, the hydrophilic 2′-O-hydroxyl group is masked with a hydrophobic methyl group.
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Figure 2
Pseudouridine is formed from uridine by base rotation
around the N3-C6 axis after cleavage of the N1-C1 glycosyl bond.
Pseudouridine contains an extra imino group in comparison with its
parent nucleotide.
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In rRNAs and snRNAs, the precise function
of modified nucleotides is not yet defined. However, since the altered
nucleotides cluster around functionally important regions of these RNAs
and show a striking evolutionarily conservation, it is expected that
they are fundamental to the faithful function of both rRNAs and snRNAs.
The most prevalent RNA modifications are the 2′-O-ribose methylation of
the four classical ribonucleotides and conversion of uridines into
pseudouridine, as shown in Figure 1 and Figure 2.
Mammalian 18S, 5.8S and 28S rRNAs together carry about 100
pseudouridines and 115 2′-O-methyl groups. Since the numerous
2′-O-methylated nucleotides and pseudouridines occupy diverse sequence
and structural environments, the molecular mechanism underlying their
site-specific synthesis has remained an enigma for almost a
half-century.
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Formation of mature rRNAs takes place in
a subnuclear organelle, the nucleolus. The 18S, 5.8S and 28S rRNAs are
processed from a long primary rRNA transcript (pre-rRNA) containing
long noncoding spacer and flanking sequences. Pseudouridylation and
2′-O-ribose methylation of the 18S, 5.8S and 28S rRNAs occurs before
nucleolytic processing of the pre-rRNA. New insight into the mechanism
of these rRNA modifications followed from the discovery of
intron-encoded small nucleolar RNAs (snoRNAs) in the early 1990s. This
discovery caused great excitement amongst molecular biologists since
the intronic snoRNAs, instead of being transcribed from independent
transcription units, are processed from pre-mRNA introns. Soon after
the discovery of the first intronic snoRNA (1366), it became
apparent that intron processing is a general mechanism for production
of snoRNAs and that the nucleolus contains an unexpected number of
snoRNAs. The nucleolar localization of intronic snoRNAs suggested that
they might function in some aspects of rRNA maturation. This proposal
was strongly supported by the fact that many newly discovered snoRNAs
carried 10-21 nucleotide long sequences that are perfectly
complementary to the 18S and 28S rRNAs (for review see 1361).
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The experiment: Ribose-methylation of rRNAs
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In the mid 1990s, when I moved to
Toulouse, my major interest was in understanding the nucleolar function
of intronic snoRNAs. In hopes of learning more about the structure and
possible function of this class of RNAs by characterizing several novel
snoRNAs, we constructed a cDNA library of human intron-encoded snoRNAs.
While identification of a new snoRNA had been a time-consuming and
laborious task before, a systematic sequence analysis of our cDNA
library provided us with sequences of about 50 novel human snoRNAs (741).
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Figure 3
Site-specific 2′-O-ribose methylation of rRNAs is
directed by box C/D snoRNAs. C/D box snoRNA:rRNA pairing places the D
or D′ box of the snoRNA at a constant position from the 2′-O-methylated
nucleotide.
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A large subset of the newly identified
snoRNAs carried one or sometimes two sequence motifs complementary to
human rRNAs, as shown in Figure 3.
The antisense sequences were adjacent to short sequence elements
evolutionarily conserved amongst snoRNAs, called the D or D′ box
(consensus CUGA) and the C or C′ box (consensus UGAUGA).
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By the end of the 1980s, most 2′-O-methyl
groups had been mapped both on mammalian and yeast rRNAs, thanks to the
heroic effort of the laboratory of Ted Maden (for review see 1369).
When we inspected the putative base-pairing interactions between the
new antisense snoRNAs and the complementary rRNA sequences, two
observations became apparent. First, the distribution of ribosomal
2′-O-methylated nucleotides largely correlated with the binding sites
of snoRNAs. More importantly, we also noticed that in the putative
snoRNA-rRNA interaction, the ribosomal nucleotide destined for
2′-O-methylation has an invariant location; it always faces the fifth
nucleotide upstream from the D or D′ box of the snoRNA, as shown in Figure 3.
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We proposed a model in which
2′-O-methylation of rRNAs is guided by box C/D snoRNAs. A transient
base-pairing interaction would place the D or D′ box of the snoRNA at a
fixed position with respect to the ribosomal target nucleotide. A
putative 2′-O-methyltransferase which would likely bind to the D or D′
box of the snoRNA would rely on this structural information to select
the ribosomal target nucleotide located five base pairs from the D or
D′ box.
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Figure 4
Ribose-methylation of the C1436 residue in the yeast 25S
rRNA is directed by the U24 snoRNA. Base-pairing interaction of the
yeast U24 snoRNA and 25S rRNA can position the C1436 residue (circled)
for 2′-O-methylation. An altered version of the U24 snoRNA (U24m) is
predicted to direct 2′-O-methylation of the U1437 residue (underlined).
Ribose-methylation was tested in 25S rRNAs obtained from wild-type
(lane WT) and mutant cells in which the U24 locus had been disrupted
(lane ΔU24) derivatives of the ΔU24 strain which expressed either the
host gene of the U24 intronic snoRNA (lane HOST), the U24 snoRNA (lane
U24) or the mutant U24m snoRNA (lane U24m). The U24m construct carries
a C80 deletion. Lanes C, U, A and G are sequencing ladders of the yeast
25S rRNA.
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Figure 5
Primer extension assay for 2′-O-methylated nucleotides.
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We sought to experimentally validate the proposed model of
snoRNA-directed 2′-O-methylation by using the yeast Saccharomyces cerevisiae.
Our model predicted that the antisense element preceding the D box of
the yeast U24 snoRNA can position the C1436 residue in the 25S rRNA for
2′-O-methylation (Figure 4).
To test whether the U24 snoRNA functions in 2′-O-methylation of 25S
rRNA, the U24 snoRNA gene and its host gene (HOST) were depleted in a
haploid yeast strain by classical yeast gene replacement technology,
resulting in the ΔU24 strain. The state of 2′-O-methylation of the
C1436 residue in the 25S rRNA was tested in both the wild-type (WT) and
the disruption mutant (ΔU24) yeast strains. Figure 5
shows our primer extension assay, in which partially hydrolyzed 25S
rRNA was used as a template, and 2′-O-methylated nucleotides appeared
as "gaps" in the ladder of the extension products.
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As seen in Figure 4,
the C1436 residue was 2′-O-methylated in the 25S rRNA obtained from the
wild-type strain (lane WT), but it was unmodified in the disruption
mutant strain (lane ΔU24), demonstrating that either the U24 snoRNA or
its host gene is essential for ribose-methylation of the C1436 residue.
Since restoration of the expression of the U24 snoRNA in the ΔU24
strain (lane U24), but not its host gene (lane HOST), could reestablish
2′-O-methylation of the C1436 residue, we concluded that the U24 snoRNA
is required for the 2′-O-methylation of the yeast 25S rRNA. Finally, we
tested a strain expressing an altered version of the U24 snoRNA in the
ΔU24 background. In this altered version of U24, U24m, the distance
between the D box and the C1436 residue was reduced to four nucleotides
and the neighboring U1437 residue was 2′-O-methylated (lane U24m). This
demonstrated that ribosomal nucleotides located five base pairs from
the D box are selected for 2′-O-methylation, and that the U24 snoRNA
was acting as a guide RNA for the modification of 25S rRNA.
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The experiment: Pseudouridylation of rRNAs
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Figure 6
Site-specific pseudouridine formation in rRNAs is guided
by box H/ACA snoRNAs. The snoRNA and rRNA form a complex pseudoknot
structure in which the substrate uridine (Ψ) occupies an invariant
position at the base of the upper stem closing the pseudouridine
recognition loop of the snoRNA.
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In 1996, Fournier and his colleagues
noticed that snoRNAs lacking the C and D boxes contain an
evolutionarily conserved ACA motif located three nucleotides from the
3′ end of the RNA (1216). They concluded that most snoRNAs
belong to one of two distinct families, depending on the presence of
the box C/D or box ACA motif. Indeed, inspection of our newly
identified intronic snoRNAs confirmed that several RNAs, although
lacking C and D boxes, featured a 3′-terminal ACA box. Structural
probing of a novel box ACA snoRNA, followed by a systematic computer
modeling of all mammalian and yeast box ACA snoRNAs revealed that this
class of snoRNAs share a conserved two-dimensional structure shown in Figure 6,
consisting of two hairpin structures and another conserved sequence motif, the H box
(consensus ANANNA) (1217). The box H/ACA snoRNAs were found to be specifically
associated with an evolutionarily conserved nucleolar protein, Gar1p (1216; 1217).
Intriguingly, in collaboration with Michou Ferrer's group, we showed
that the Gar1 box H/ACA snoRNP protein is essential for the global
pseudouridylation of yeast rRNAs (1219). This observation strongly suggested that
the box H/ACA snoRNAs function in rRNA pseudouridylation.
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By 1997, Ofengand and his colleagues
determined the positions of all pseudouridines in yeast 18S, 25S and
human 28S rRNAs (reviewed in 1370). For human 18S rRNA,
distribution of pseudouridines had been reported before (1369).
We scrutinized all box H/ACA snoRNAs for complementarity to rRNA sequences
at known pseudouridylation sites (1218).
We found that the majority of box H/ACA snoRNAs possess at least one or
sometimes two pairs of short sequence motifs which can base-pair with
rRNA sequences flanking a reported pseudouridylation site. The putative
rRNA recognition sequences occupy the opposite strands of internal
loops in the 5′- and/or 3′-terminal hairpin structure of the snoRNA (Figure 6).
In the putative snoRNA-rRNA interaction the uridine residue selected
for pseudouridylation is placed at the base of the upper stem flanking
the pseudouridylation guide loop of the snoRNA. In this
"pseudouridylation pocket," the substrate uridine is located about 14
nucleotides upstream of the H or ACA box of the snoRNA.
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Figure 7
Gene disruption and restoration experiments demonstrate
that pseudouridylation of the U1003 residue in the yeast 25S rRNA is
guided by base pairing with the box H/ACA snoRNA, snR5.
Pseudouridylation of 25S rRNAs purified from wild-type yeast cells
(lane WT), from cells lacking a functional SNR5 gene (lane ΔsnR5 ) as
well as from ΔsnR5 cells expressing an exogenous SNR5 gene (lane
snR5rest) . Lanes U, G, C and A show sequencing ladders of the yeast
25S rRNA.
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Figure 8
CMC-reverse transcriptase assay for pseudouridylation.
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To verify the proposed pseudouridylation model, the yeast SNR5
gene encoding the putative snR5 pseudouridylation guide RNA was
depleted in a haploid yeast strain. The proposed pseudouridylation
pocket in the 3′-terminal hairpin of the snR5 snoRNA should position
the U1003 residue in the yeast 25S rRNA for pseudouridylation, as seen
in Figure 7. The pseudouridylation status of the 25S rRNA was assayed by the
CMC-reverse transcriptase approach shown in Figure 8. Conversion of the U1003
residue into pseudouridine was monitored in 25S rRNAs derived from the wild-type (Figure 7,lane WT)
and the snR5-depleted (lane ΔsnR5) strains. Depletion of snR5
abolished pseudouridylation of the U1003 residue, but did not affect
pseudouridine synthesis at other known pseudouridylation sites in the
yeast 25S rRNA (for example at U959, U965, U985, and U989). Moreover,
restoration of the expression of snR5 in the ΔsnR5 strain (lane
snR5rest) reestablished the site-specific pseudouridylation of U1003,
demonstrating that conversion of the U1003 residue into pseudouridine
is guided by the snR5 box H/ACA snoRNA. In an independent study, the
Fournier laboratory showed that 10 yeast box H/ACA snoRNAs could be
correlated with specific rRNA pseudouridylation reactions (742),
providing solid evidence for the notion that box H/ACA snoRNAs function
as guide RNAs in the site-specific pseudouridylation of eukaryotic
rRNAs.
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The legacy
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In eukaryotic rRNAs, the site-specific synthesis of the "fifth ribonucleotide,"
pseudouridine (1364),
and the equally abundant 2′-O-ribose-methylated nucleotides is guided
by snoRNAs. Although the guide snoRNAs are associated with a set of
proteins, the RNA component of the particle provides all the
information necessary for selection of the correct ribosomal nucleotide
for 2′-O-methylation and pseudouridylation. Consistent with this
conclusion, by manipulating the rRNA recognition motifs of
2′-O-methylation and pseudouridylation guide snoRNAs, novel
modification sites have been introduced into mammalian and yeast rRNAs (1363;
1362). Recently, snoRNAs have been demonstrated to also function in 2′-O-methylation
of spliceosomal snRNAs (1368; 1365),
demonstrating that the snoRNA-mediated RNA modification is a
more widespread strategy and is not simply confined to rRNAs.
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Apparently, adoption of the
snoRNA-guided modification mechanism provides many advantages for
eukaryotic cells. Eubacterial rRNAs contain only a few modified
nucleotides which are synthesized by specific protein enzymes. In
eukaryotes, instead of expressing hundreds of protein enzymes, a single
snoRNA-associated pseudouridine synthase (Nap57p/Cbf5p) and
2′-O-methyltransferase (fibrillarin) can accomplish the site-specific
synthesis of myriad modified nucleotides in rRNAs, snRNAs and most
probably other cellular RNAs. While evolution of protein enzymes is
ponderous and highly dependent on the preexisting modification sites,
the snoRNA-guided modification system is much more flexible and can
evolve very rapidly. Random mutations in the rRNA recognition motif can
easily give rise to a new guide snoRNA directing modification of a
novel rRNA site. As a consequence, the snoRNA-guided pseudouridylation
and 2′-O-methylation systems can continuously survey rRNA sequences
during evolution to introduce novel functionally advantageous
modifications into eukaryotic ribosomes.
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The author
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Tamás Kiss is Directeur de Recherche at the French medical research
organization, INSERM (Institut National de la Santé et de la Recherche
Médicale). He graduated from the Faculty of Natural Sciences at
University József Attila, Szeged, Hungary. He received undergraduate
and postgraduate training at the Biological Research Center of the
Hungarian Academy of Sciences, Szeged, where he studied the function
and expression of plant small nuclear RNAs with Ferenc Solymosy. His
postdoctoral research with Witold Filipowicz at the Friedrich Miescher
Institute, Basel, Switzerland, focused on the understanding of the RNA
polymerase selection of plant small nuclear RNA genes. Later, being
amongst the first scientists who discovered intron-encoded small
nucleolar RNAs, his interest turned to the biogenesis and function of
this fascinating group of small RNAs. He is a Doctor of the Hungarian
Academy of Sciences and an elected member of the European Molecular
Biology Organization.
Tamás Kiss
Laboratoire de Biologie Moléculaire Eucaryote du CNRS
Université Paul Sabatier
118 route de Narbonne
31062 Toulouse, France
Phone: (33) 5 61 33 59 91
Fax: (33) 5 61 33 58 86
E-mail: tamas@ibcg.biotoul.fr
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Last Revised on September 10, 2004
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©Jones and Bartlett Publishers (2007)
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