Aminoglycoside Antibiotics Are Able To Specifically Bind the 5‘-Untranslated Region of Thymidylate Synthase Messenger RNA

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Abstract
The translational initiation codon for thymidylate synthase (TS) mRNA is located in a unique stem−loop structure which contains an internal cytosine-cytosine (CC) bubble. This stem−loop structure is thought to be important in the regulation of TS translation, which is itself an important target for anticancer drugs, such as 5-fluorouracil. Internal bubble or bulge structures are candidate receptors for the aminoglycoside antibiotics. It is shown here that aminoglycosides bind in a specific and saturable fashion with dissociation constants of approximately 1 μM to a TS mRNA site 1 construct and that the binding site for the aminoglycosides is located in the CC bubble region. In fact, the CC bubble, when grafted into other stem−loop structures, confers aminoglycoside binding on them. These studies reveal an additional binding domain for aminoglycosides and also suggest how novel anti-cancer drugs might be designed that affect TS mRNA translation rather than enzyme function.