A discontinuous hammerhead ribozyme embedded in a mammalian messenger RNA

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Abstract
An active ribozyme which can regulate gene expression was previously identified in bacteria, but whether there are similar regulatory ribozymes in eukaryotes was unknown. In this study, Martick et al. identify active ribozymes in the 3' UTRs of several rodent lectin genes. Unusually, these hammerhead ribozymes have a split structure, such that both halves must self-cleave and reassemble to give activity. Some data show that these ribozymes may potentially regulate gene expression, although further work will be necessary to confirm this function. Active ribozymes are identified in the 3' UTRs of several rodent lectin genes. These have a split structure, such that both halves must self-cleave and reassemble to give activity, and could potentially regulate gene expression. Structured RNAs embedded in the untranslated regions (UTRs) of messenger RNAs can regulate gene expression. In bacteria, control of a metabolite gene is mediated by the self-cleaving activity of a ribozyme embedded in its 5′ UTR1. This discovery has raised the question of whether gene-regulating ribozymes also exist in eukaryotic mRNAs. Here we show that highly active hammerhead ribozymes2,3 are present in the 3′ UTRs of rodent C-type lectin type II (Clec2) genes4,5,6,7. Using a hammerhead RNA motif search with relaxed delimitation of the non-conserved regions, we detected ribozyme sequences in which the invariant regions, in contrast to the previously identified continuous hammerheads8,9,10, occur as two fragments separated by hundreds of nucleotides. Notably, a fragment pair can assemble to form an active hammerhead ribozyme structure between the translation termination and the polyadenylation signals within the 3′ UTR. We demonstrate that this hammerhead structure can self-cleave both in vitro and in vivo, and is able to reduce protein expression in mouse cells. These results indicate that an unrecognized mechanism of post-transcriptional gene regulation involving association of discontinuous ribozyme sequences within an mRNA may be modulating the expression of several CLEC2 proteins that function in bone remodelling and the immune response of several mammals.