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Nucleic Acids Research 2006 34(3):853-864; doi:10.1093/nar/gkj490
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Published online 6 February 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
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Article

The dicistronic RNA from the mouse LINE-1 retrotransposon contains an internal ribosome entry site upstream of each ORF: implications for retrotransposition

Patrick Wai-Lun Li1,2, Jinfang Li1, Stephanie L. Timmerman4, Les A. Krushel3–,5 and Sandra L. Martin1–,3,*

1Cell and Developmental Biology, University of Colorado School of Medicine 12801 E. 17th Avenue, Aurora, CO 80010, USA 2Human Medical Genetics Program, University of Colorado School of Medicine 12801 E. 17th Avenue, Aurora, CO 80010, USA 3Program in Molecular Biology, University of Colorado School of Medicine 12801 E. 17th Avenue, Aurora, CO 80010, USA 4Biochemistry and Molecular Genetics, University of Colorado School of Medicine 12801 E. 17th Avenue, Aurora, CO 80010, USA 5Department of Pharmacology, University of Colorado School of Medicine 12801 E. 17th Avenue, Aurora, CO 80010, USA

*To whom correspondence should be addressed. Tel: +1 303 724 3467; Fax: +1 303 724 3420; Email: sandy.martin{at}uchsc.edu

Received November 29, 2005. Revised January 18, 2006. Accepted January 18, 2006.

Most eukaryotic mRNAs are monocistronic and translated by cap-dependent initiation. LINE-1 RNA is exceptional because it is naturally dicistronic, encoding two proteins essential for retrotransposition, ORF1p and ORF2p. Here, we show that sequences upstream of ORF1 and ORF2 in mouse L1 function as internal ribosome entry sites (IRESes). Deletion analysis of the ORF1 IRES indicates that RNA structure is critical for its function. Conversely, the ORF2 IRES localizes to 53 nt near the 3' end of ORF1, and appears to depend upon sequence rather than structure. The 40 nt intergenic region (IGR) is not essential for ORF2 IRES function or retrotransposition. Because of strong cis-preference for both proteins during L1 retrotransposition, correct stoichiometry of the two proteins can only be achieved post-transcriptionally. Although the precise stoichiometry is unknown, the retrotransposition intermediate likely contains hundreds of ORF1ps for every ORF2p, together with one L1 RNA. IRES-mediated translation initiation is a well-established mechanism of message-specific regulation, hence, unique mechanisms for the recognition and control of these two IRESes in the L1 RNA could explain differences in translational efficiency of ORF1 and ORF2. In addition, translational regulation may provide an additional layer of control on L1 retrotransposition efficiency, thereby protecting the integrity of the genome.

Present address: Jinfang Li, Replidyne, 1450 Infinite Drive, Louisville, CO 80027, USA


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