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combinations of sequences in the J4/2 region should appear in approxi-
mately equal distributions. That this is not the case points to common ances-
tral sequences that have been subjected to randommutations to unconserved
portions to establish the variability seen today.
Furthermore, HDV-like ribozymes are found with and without a J1.1/4
region. Ribozymes without this region are quite heterogeneous in nucleo-
tide composition at the top of the P4 helix, whereas those with a J1.1/4
region contain almost exclusively an A-G mispair at this location. In the
crystal structure of the genomic HDV ribozyme, the A43 and G74 residues
are base paired, and G74 forms additional tertiary contacts with other nucle-
otides in the J1.1/4 region. These interactions provide a number of stabiliz-
ing effects for the ribozyme. Therefore, it is unlikely that they would be lost
during the evolution of the sequence. Rather, the presence or absence of a
J1.1/4 region might provide a fine-tuning mechanism for the self-cleavage
rate of the ribozyme following multiple, convergent paths of evolution to an
HDV-like core. The P3, L3, and P1.1 core regions of the ribozymes are all
very similar, and identical between closely related retrotransposon
ribozymes regardless of the presence of a J1.1/4 region. This is indicative
of the minimal sequence space that the core regions can occupy, whereas
the remainder of the motif can arise from a diverse set of nucleotides so long
as proper base pairing is maintained. Combined, these data allow for a model
in which the HDV ribozyme motif evolved independently in several evo-
lutionary lines and subsequently spread among closely related species.
Although the evolutionary path of HDV-like ribozymes remains to be
determined, the widespread nature of this motif cannot be denied. The
motif has been identified across all kingdoms of life except Archaea, and
in a variety of biological roles including retrotransposition and genome
processing, with putative roles in mRNA stability and translation regulation.
Recently, hammerhead ribozymes have also been identified in a variety of
species, including mammals.
5,6,110
These data indicate that the self-cleaving
ribozymes, and likely ribozymes in general, are much more common in bio-
logical systems than previously expected.
REFERENCES
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