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J. Biol. Chem., Vol. 281, Issue 2, 733-743, January 13, 2006

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The Flatworm Spliced Leader 3'-Terminal AUG as a Translation Initiator Methionine^*

Guofeng Cheng, Leah Cohen, David Ndegwa, and Richard E. Davis1

From the Departments of Pediatrics and Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045 and the Department of Biology, City University of New York Graduate Center, College of Staten Island, Staten Island, New York, 10314

Spliced leader (SL) RNA trans-splicing contributes the 5' termini to mRNAs in a variety of eukaryotes. In contrast with some transsplicing metazoan groups (e.g. nematodes), flatworm spliced leaders are variable in both sequence and length in different flatworm taxa. However, an absolutely conserved and unique feature of all flatworm spliced leaders is the presence of a 3'-terminal AUG. We previously suggested that the Schistosoma mansoni spliced leader AUG might contribute a required translation initiator methionine to recipient mRNAs. Here we identified and examined trans-spliced cDNAs from a large set of newly available schistosome cDNAs. 28% of the trans-spliced cDNAs have the SL AUG in-frame with the major open reading frame of the mRNA. We identified over 40 cDNAs (40% of the SL AUG in-frame clones) that require the SL AUG as an initiator methionine to synthesize phylogenetically conserved N-terminal residues characteristic of orthologous proteins. RNA transfection experiments using several schistosome stages demonstrated that the flatworm SL AUG can serve as a translation initiator methionine in vivo. We also present in vivo translation studies of the schistosome initiator methionine context and the effect of the spliced leader AUG added upstream and out-of-frame with the main open reading of recipient mRNAs. Overall, our data have provided evidence that another function of flatworm spliced leader trans-splicing is to provide some recipient mRNAs with an initiator methionine for translation initiation.

Received for publication, June 27, 2005 , and in revised form, September 27, 2005.

^* This work was supported by grants from Ellison Medical Foundation (Grant ID-IA-0037) and the National Institutes of Health (Grant AI49558) and by UCHSC startup funds (to R. E. D.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table showing schistosome mRNAs using the SL AUG as an initiator methionine.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Mail Stop 8101, P. O. Box 6511, 12801 East 17th Ave., Aurora, CO 80045. Tel.: 303-724-3226; Fax: 303-724-3215; E-mail: Richard.Davis{at}uchsc.edu.

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