Beyond the Identification of Transcribed Sequences:
Functional, Evolutionary and Expression Analysis
12th International Workshop
October 25-28, 2002
Washington, DC

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3' Untranslated Regions and Selenocysteine Incorporation: From Modulation of Translation to a Novel Single Nucleotide Polymorphism

Stéphane Villette1, G. Bermano3, John R. Arthur2 and John E. Hesketh1*
1School of Cellular & Molecular Biosciences, University of Newcastle,Newcastle upon Tyne,NE1 7RU, UK. 2 Division of Cell Integrity, Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, Scotland, UK. 3 University of Aberdeen Medical School, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
Telephone: 00-44-191-222-8744
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The 3’ untranslated region (3’UTR) of mRNAs has important regulatory functions. As well as determining mRNA translation, localisation and stability, in a limited number of mRNAs the 3’UTR is important for incorporation of Selenium (Se) into proteins as the 21st amino-acid selenocysteine. Se is an essential micronutrient for human health; limited intake has been linked to cancer and heart disease. The biological roles of Se are attributed to its presence in a range of 20-30 selenoproteins including the cytosolic, gastrointestinal and phospholipid hydroperoxide glutathione peroxidases (GPX1, GPX2 and GPX4) which protect cells from oxidative stress. In addition, it has been suggested that GPX1/GPX4 may play a role in regulation of leukotriene biosynthesis and thus inflammation. In eukaryotes Se incorporation requires a stem-loop (the SECIS element) within the 3’UTR. If supply of Se is limiting in the diet or culture medium then selenoprotein synthesis is modulated but not all selenoproteins are affected equally; there is a tissue-specific prioritisation of the available Se. Such prioritisation depends on 3’UTR sequences (see Bermano et al, 1997; Hesketh & Villette, 2002) . It is therefore possible that genetic variation between individuals in the gene regions corresponding to 3’UTR sequences could cause different patterns of Se incorporation and different susceptibility to disease. Recently we found that the region of the GPX4 gene corresponding to the 3’UTR contained a T/C variant at position 718. The distribution of this SNP in our population was 34% CC, 25% TT and 41% TC (Villette et al, 2002). Individuals of different genotype exhibited significant differences in the levels of lymphocyte 5- lipoxygenase total products, C718 showing increased levels of those products compared to T718 and T/C718 (36% and 44% increases respectively). The data suggest that the SNP718 that we have identified has functional consequences.

Hesketh JE & Villette,S (2002) Proc. Nutr. Soc 61, 1-10

Villette et al. (2002) Blood Cells. Mol. Disease. in press

We thank our colleagues who have contributed to the work reviewed in this paper and Food Standards Agency and Scottish Executive Environment and Rural Affairs Department (SEERAD) for financial support.

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