Occupancy Activated Destabilization

RNA molecules regulate their own metabolism. A number of structural features of RNA aie known to influence stability, various processing events, subcellular distribution, and transport. It is likely that, as RNA intermediary metabolism is better understood, many other regulatory features and mechanisms will be identified.

4.2.1 5'-Capping. A key early step in RNA processing is 5'-capping (Fig. 5.1). This stabilizes pre-mRNA and is important for the stability cf mature mRNA. It also is important in bindingto the nuclear matrix and transport of mRNA out of the nucleus. Because the structure cf the cap is unique and understood, it presents an interesting target. Several oligonucleotides that bind near the cap site have been shown to be active, presumably by inhibiting the binding of proteins required to cap the RNA For example, the synthesis of SV40 T-antigen was reported to be most sensitive to an oligonucleotide linked to polylysine and targeted to the 5'-cap site of RNA (122). How ever, again, in no published study has this putative mechanism been rigorously demonstrated. In fact, in no published study have the oligonucleotides been shown to bind to the sequences for which they were designed.

In our laboratory, we have designed oligonucleotides to bind to 5'-cap structures and reagents to specifically cleave the unique 5'-cap structure (123). These studies demonstrated that 5'-cap-targeted oligonucleotides were capable of inhibiting the binding of the translation initiation factor eIF-4a (124).

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