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Nucleic Acids Research 2005 33(20):6593-6602; doi:10.1093/nar/gki958
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Published online 28 November 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Survey and Summary

A second look at cellular mRNA sequences said to function as internal ribosome entry sites

Marilyn Kozak*

Department of Biochemistry, Robert Wood Johnson Medical School 675 Hoes Lane, Piscataway, NJ 08854, USA

*Tel: +1 732 235 5355; Fax: +1 732 235 5356; Email: kozakma{at}umdnj.edu

Received October 5, 2005. Accepted October 26, 2005.

This review takes a second look at a set of mRNAs that purportedly employ an alternative mechanism of initiation when cap-dependent translation is reduced during mitosis or stress conditions. A closer look is necessary because evidence cited in support of the internal initiation hypothesis is often flawed. When putative internal ribosome entry sequences (IRESs) are examined more carefully, they often turn out to harbor cryptic promoters or splice sites. This undermines the dicistronic assay, wherein IRES activity is measured by the ability to support translation of the 3' cistron. Most putative IRESs still have not been checked carefully to determine whether the dicistronic vector produces only the intended dicistronic mRNA. The widespread use of the pRF vector is a major problem because this vector, which has Renilla luciferase as the 5' cistron and firefly luciferase as the 3' cistron, has been found to generate spliced transcripts. RNA transfection assays could theoretically circumvent these problems, but most candidate IRESs score very weakly in that test. The practice of calling even very weak results ‘positive’ is one of the problems discussed herein. The extremely low efficiency of putative IRESs is inconsistent with their postulated biological roles.

‘...if it is a Miracle, any sort of evidence will answer, but if it is a Fact, proof is necessary’

—Mark Twain, Letters from the Earth


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