IRESs and Negative Data
Nature Precedings represents a step forward for disseminating experimental results in the internet age. Especially ‘negative’ results, that might not have gotten published otherwise, but is extremely helpful to other researchers in trying to avoid making the same mistakes. Refutation of a hypothesis, while not a discovery, is the goal of the well-planned experiment in the trenches of science.
An outstanding example of such a Preceding can be found in the manuscript Internal ribosomal entry site lacks secondary structure by Xuhua Xia of the University of Ottawa’s Department of Biology.
How internal ribosomal entry sites (IRESs) work as translational start-points is an interesting question for two reasons. First, as the author notes, it could help us to understand a crucial aspect of microbial parasitism. It could help to understand how pathogens such as HIV hijack the regular mRNA translational machinery during infection. A good deal is already known about viral IRES mechanisms and what initiation factors they interact with, but this would be better understood if we could contrast viral IRES mechanisms with their cellular counterparts. Second, IRESs have become more commonly used in molecular cloning of recombinant plasmids. Such sequences represent a useful tool in tweaking gene expression for all sorts of reasons, including a great many biotech uses of biomolecular engineering.
In this paper, Xuhua Xia reports that:
The search for mechanisms of translational regulation has yielded many experimentally identified internal ribosome entry sites (IRES). Because of the lack of sequence similarity among the experimentally IRESs, it is widely assumed that IRESs posses stable secondary structure allowing them to interact with the components of the translation machinery. Contrary to this view, here we show that IRES activity in nine yeast IRESs, mapped to 60 nt immediately upstream of the initiation AUG, is strongly associated with the lack of secondary structure of IRESs.
So while it makes a lot of sense that IRESs work by forming some sort of secondary structure with which to interact with ribosomes or their factors, the evidence presented in this Preceding suggests otherwise.
I guess it’s back to the drawing board.
- Xia, Xuhua. Internal ribosomal entry site lacks secondary structure Available from Nature Precedings (2007)
- Pelletier J, Sonenberg N (1988). Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature 334 (6180): 320-5. DOI:10.1038/334320a0
- Kozak M (2005). A second look at cellular mRNA sequences said to function as internal ribosome entry sites. Nucleic Acids Res. 33 (20): 6593-602. DOI:10.1093/nar/gki958
molecular biology
