THE ROLE OF SELENIUM IN CELLULAR METABOLISM

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The element selenium is required in the diet of mammals and excesses or deficiencies of this element in the diet within a narrow range are detrimental to health. A wide range of evidence supports the involvement of selenium in preventing cancer and heart disease and a role in delaying the onset of the aging process. As selenium exerts its cellular effects, at least in part, as the amino acid selenocysteine in protein, we are trying to elucidate the mechanism by which selenocysteine is incorporated into protein. The biosynthesis of selenocysteine in cells occurs on its tRNA which is first aminoacylated with serine. In the past year, we have found several new selenocysteine tRNAs in human cell lines and these results raise the possibility that some of these isoacceptors may arise as a result of editing. Further, we have shown that the TATA box and proximal sequence element are sufficient for basal level transcription of the gene. These results differ from all other known eukaryotic genes which contain control elements within their genes. The transcription start site was found to be determined by the distance between the TATA box and the start site. The Xenopus selenocysteine tRNA gene was found to be transcribed more like Pol II than Pol III genes even thought this gene is transcribed by Pol III. Seryl-tRNA-[Ser]Sec and selenocysteyl- tRNA-[Ser]Sec were examined for their ability to donate the corresponding amino acid to protein. Serine was donated in response to the codon, UGA, to suppress this codon, while selenocysteine was donated only in vivo in response to a selenocystine UGA codon. These results provide strong evidence that a specific elongation factor is involved in the insertion of selenocysteine into protein in response to specific selenocysteine UGA codons. Selenocysteine and serine tRNAs were found to be aminoacylated by the same seryl-tRNA synthetase and these tRNAs share very similar sites of identity. Selenocysteine can be inserted into protein in response to UAA and UUA codons, provided the selenocysteine tRNA contains an anticodon complementary to the corresponding codon which very importantly shows that UGA is not required.