The Hammerhead Ribozyme: Structure, Catalysis, and Gene Regulation - Progress in Molecular Biology and Translational Science - page 14

Hence, it appears that the functional groups identified in the crystal
structure as the main participants in acid-base catalysis indeed do so.
4. HAMMERHEAD RIBOZYMES IN MAMMALIAN GENE
REGULATION
Discovery of conserved mammalian hammerhead ribozymes suggests
that the hammerhead motif's biological role extends beyond processing of
satellite RNA and viroid replication products, and into the dominion of cel-
lular functions. 9,10 Uncovered by bioinformatic searches of available
genomes, the new class of hammerhead ribozymes is found in 3 0 untranslated
regions (UTRs) of several mammalian C-type lectin type II (CLEC2)
genes. 63 The formation of active hammerhead ribozymes between the stop
codon and the polyadenylation (polyA) signal sequence ( Fig. 1.3 ) leads to
cis-cleavage of the 3 0 UTR and reduction of associated gene expression. 9,10
Significantly, these sequences represent full-length ribozymes including ter-
tiary interactions necessary for physiologically relevant catalytic rates. Here,
we provide an overview of the mammalian mRNA-associated CLEC2
ribozymes.
To date, 12 CLEC2 hammerhead ribozymes have been identified in 9
mammalian species ( Fig. 1.4 ). Two structures are found in mouse, three
in rat, and one in each of the following mammalian genomes: tree shrew,
hedgehog, horse, elephant, cow, dog, and platypus. 9,10 All 12 are located
immediately downstream of genomic sequences that share varying degrees
of homology with the CLEC2 gene family. Two hammerhead ribozymes in
mouse CLEC genes (m CLEC2d - and m CLEC2e ) and one in rat
(r CLEC2D11 ) reside within the 3 0 UTRs of known protein coding genes.
The incomplete proteome annotation of the other seven species prevents
verification that their hammerhead ribozymes are embedded in mature tran-
scripts. However, the horse and platypus ribozymes are located within the
approximated 3 0 UTRs of predicted CLEC2-like genes. The best-
characterized CLEC2 family member resides in m CLEC2d . This gene
encodes a cell surface ligand (CLRB) that is recognized by natural killer
(NK) cells through an inhibitory NKR-P1 receptor. 64 Engagement of
the NK cell-associated receptor with the CLRB ligand initiates an inhibitory
signal such that the loss of CLRB expression increases NK cell-mediated
cytotoxicity.
All 12 ribozymes have a similar global arrangement: They are type III
hammerheads that contain large, nonconserved, intervening sequences in