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J. Biol. Chem., Vol. 282, Issue 35, 25613-25622, August 31, 2007

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Leaky Scanning and Scanning-independent Ribosome Migration on the Tricistronic S1 mRNA of Avian Reovirus^*

From the Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada

The S1 genome segments of avian and Nelson Bay reovirus encode tricistronic mRNAs containing three sequential partially overlapping open reading frames (ORFs). The translation start site of the 3'-proximal ORF encoding the C protein lies downstream of two ORFs encoding the unrelated p10 and p17 proteins and more than 600 nucleotides distal from the 5'-end of the mRNA. It is unclear how translation of this remarkable tricistronic mRNA is regulated. We now show that the p10 and p17 ORFs are coordinately expressed by leaky scanning. Translation initiation events at these 5'-proximal ORFs, however, have little to no effect on translation of the 3'-proximal C ORF. Northern blotting, insertion of upstream stop codons or optimized translation start sites, 5'-truncation analysis, and poliovirus 2A protease-mediated cleavage of eIF4G indicated C translation derives from a full-length tricistronic mRNA using a mechanism that is eIF4G-dependent but leaky scanning- and translation reinitiation-independent. Further analysis of artificial bicistronic mRNAs failed to provide any evidence that C translation derives from an internal ribosome entry site. Additional features of the S1 mRNA and the mechanism of C translation also differ from current models of ribosomal shunting. Translation of the tricistronic reovirus S1 mRNA, therefore, is dependent both on leaky scanning and on a novel scanning-independent mechanism that allows translation initiation complexes to efficiently bypass two functional upstream ORFs.

Received for publication, May 4, 2007 , and in revised form, June 29, 2007.

^* This research was supported in part by a grant from the Natural Sciences and Engineering Research Council of Canada (to R. 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.

¹ Supported by a scholarship from the Nova Scotia Health Research Foundation.

² Supported by scholarships from the Natural Sciences and Engineering Research Council of Canada and the Killam Foundation.

³ To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Tupper Medical Bldg., Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada. Tel.: 902-494-6770; Fax: 902-494-5125; E-mail: roy.duncan{at}dal.ca.

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