Nucleic Acids Research Advance Access published online on September 9, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp696
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Molecular Biology |
Predictable suppression of gene expression by 5'-UTR-based RNA quadruplexes
1Department of Chemistry, 2Konstanz Research School Chemical Biology (KoRS-CB) and 3Zukunftskolleg, University of Konstanz, Universitätsstr 10, 78457 Konstanz, Germany
*To whom correspondence should be addressed. Tel: +49 7531 882398; Fax: +49 7531 885140; Email: joerg.hartig{at}uni-konstanz.de
Received April 28, 2009. Revised July 15, 2009. Accepted August 6, 2009.
Four-stranded DNA and RNA quadruplexes or G4 motifs are non-B DNA conformations that are presumed to form in vivo, although only few explicit evidence has been reported. Using bioinformatics the presence of putative DNA G-quadruplexes within critical promoter regions has been demonstrated and a regulatory role in transcription has been suspected. However, in genomic DNA the presence of the complementary strand interferes with the potential to form a quadruplex motif. Contrarily RNA G4 motifs have no such limitation and consequently strong interference with gene expression is suspected. Nevertheless, experimental evidence is scarce. Here we show a well-defined structure–function relationship of synthetic quadruplex sequences in 5'-UTRs in multiple mammalian cell-lines. We establish a universal ‘translational suppressor’ effect of these motifs on gene expression at the translational level and show for the first time that specific features such as loop-length and the number of ‘GGG’-repeats further determine the suppressive impact. Moreover, a consistent and predictable repression of gene expression is observed for naturally occurring RNA G4 motifs, augmenting the functional relevance of these unusual nucleic acid structures.