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Nucleic Acids Research, 2000, Vol. 28, No. 10 2158-2163
© 2000 Oxford University Press

Specific binding of Hoechst 33258 to site 1 thymidylate synthase mRNA

Junhyeong Cho and Robert R. Rando*

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 45 Shattuck Street, Boston, MA 02115, USA

The translational initiator codon in thymidylate synthetase (TS) mRNA is located in a stem–loop structure with a CC bubble. TS is an important target for anticancer drugs. Aminoglycoside antibiotics have been shown to specifically bind to TS mRNA site 1 constructs and, furthermore, specific binding requires the non-duplex CC bubble region. It is shown here that DNA intercalating agents and DNA minor groove-binding drugs also bind to a TS mRNA site 1 construct. This binding is competitive with aminoglycosides, suggesting that the binding sites overlap. Hoechst 33258 binds with a dissociation constant of 60 nM, a value significantly lower than the ~1 µM values found for aminoglycosides. Footprinting and direct binding studies show that the CC bubble is important for binding of the Hoechst compound. However, the exact structure of the bubble is unimportant. Interestingly, mutations in regions adjacent to the bulge also affect binding. These studies point to the important role of non-duplex RNA structures in binding of the DNA minor groove binder Hoechst 33258.

* To whom correspondence should be addressed. Tel: +1 617 432 1794; Fax: +1 617 432 0471; Email: rando@hms.harvard.edu


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