Biology Reference
In-Depth Information
CLEC2 ribozymes emphasizes its importance to activity within the cellular
environment. A less appreciated structural element, the CG base pair adja-
cent to Loop II, is conserved in 11 out of 12 CLEC2 ribozymes. This inter-
action exists in identical orientation in all but one natural hammerhead
ribozyme analyzed to date and in most artificially selected species.
67
Prefer-
ential CG base pairing emphasizes the need for a reinforced helix at this posi-
tion possibly due to the nature of the adjacent loop-bulge interaction.
However underappreciated, this interaction may play an important role
in fine-tuning ribozyme function.
Homology between CLEC2 ribozymes and hammerheads used in struc-
tural and biochemical studies can explain mechanistic roles of most nucle-
otides that are conserved within the CLEC2 ribozyme group (
Fig. 1.5
).
However, other features that are unique to CLEC2 ribozymes suggest roles
intrinsic to function in their specific genomic contexts. For example,
CLEC2 ribozymes characteristically possess a long
25 bp stem III adjoin-
ing the motif to the remainder of the 3
0
UTR. Such elongated stems are
uncommon in other naturally occurring hammerhead ribozymes even
though they can stabilize catalytic structures
in vivo
.
71
Instead, the long stem
III may reflect a function specific to the location or particular mode of reg-
ulation of CLEC2 ribozyme.
Although ribozyme sequences have been found throughout divergent
genomes,
72,73
few are known to change levels of gene expression.
A single example of ribozyme-mediated gene regulation via a UTR is found
in prokaryotes.
8
The bacterial GlmS ribozyme represents one class of
riboswitches that responds to a variety of small molecule cues. The ribozyme
is encoded within the 5
0
UTR of the polycistronic mRNA, and by cleaving
within this region abrogates expression of downstream genes. In contrast,
CLEC2 hammerhead ribozymes are encoded in 3
0
UTRs that are eukaryotic
hotspots for motifs that posttranscriptionally regulate gene expression.
miRNAs and a variety of RNA-binding proteins target the 3
0
UTR and
cause changes in transcript processing, abundance, or localization.
74
More-
over, several causes of aberrant regulation of messenger RNA can be traced
to the 3
0
UTR.
75
All things considered, the hammerhead ribozyme appears
to reside in an important regulatory region that provides the possibility that
the ribozyme itself can be regulated. More recent discoveries have demon-
strated that the hammerhead ribozyme sequence is found to be ubiquitous
throughout the tree of life
76
and is possibly the most common ribozyme
sequence
77
apart fromRNase P and the peptidyl transferase of the ribosome.
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