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J. Biol. Chem., Vol. 282, Issue 36, 26026-26034, September 7, 2007

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Role of a tRNA Base Modification and Its Precursors in Frameshifting in Eukaryotes^*

From the Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037

Little is known about the role of specific base modifications of transfer RNAs. Wyosine bases are tRNA^Phe-specific modifications that are distinguished by differentiated, lateral side chains and base methylations appended to the core ring structure of a universally conserved G37, adjacent to the anticodon of Phe tRNAs. Based on previous data, we hypothesized that this modification was needed for –1 frameshifting. Using a reporter system incorporating a SCV-LA yeast virus slippery site for detecting –1 frameshifts in vivo, yeast strains were created that enabled chemical-genetic dissection of the role of different functional groups of wyebutosine that are added in a three-step post-transcriptional set of reactions. With this system, hypomodification increased Phe-specific frameshifting, with incremental changes in frameshift efficiency after specific intermediates in the progression of wyebutosine synthesis. These data combined with investigations of wild-type and hypomodified tRNA binding to ribosomes suggest that frameshift efficiency is kinetically and not thermodynamically controlled. The progressive nature of frameshift efficiency with the stage of modification is consistent with a stepwise evolution and tuning of frameshift potential. The stepwise tuning of frameshift efficiency could explain why tRNA^Phe in some eukaryotes is not fully modified but, rather, hypomodified to capture a specific frameshift potential.

Received for publication, April 24, 2007 , and in revised form, June 11, 2007.

^* This work was supported by National Institutes of Health Grant GM23562, a grant from the National Foundation for Cancer Research, and a Ruth L. Kirschstein National Research Service Award from the National Institutes of Health (to W. F. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-8970; Fax: 858-784-8990; E-mail: schimmel{at}scripps.edu.

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