MECHANISM OF SELENOPROTEIN SYNTHESIS IN EUKARYOTES

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Selenium is an essential trace element which has provoked considerable interest due to identification of a growing number of enzymes that contain the amino acid, selenocysteine. A number of these enzymes catalyze reactions that are critical to health or life. The first identified mammalian selenoenzymes, the glutathione peroxidases, catalyze detoxification of peroxides and thus, protection from oxidative stress. Another class of redox selenoenzymes, the thioredoxin reductases, play roles in proper transcription factor folding and generating reducing equivalents for deoxribonucleotide synthesis. The iodothyronine deiodinases, also selenoenzymes, catalyze thyroid hormone activation and inactivation and are thus essential to regulation of the many functions of thyroid hormone. Additional classes of selenoproteins are being discovered, with evidence for intruiging and important functions in many biological processes. In addition to cellular functions, a growing body of data is accumulating implicating selenium in the pathology of a number of viruses. Selenium status appears to affect HIV replication and the progression of AIDS, host selection for virulent strains of Coxsackie virus, and sensitivity to apoptosis in Molluscum contagiosum poxvirus infection. Studies have also implicated selenium in protection from lung, colon, and prostate cancer. Incorporation of selenocysteine into proteins requires a novel translation step in which UGA specifies selenocysteine insertion. Selenoproteins are found in eukaryotes, eubacteria, and archae, but the mechanisms of incorporation are distinct. While much is known about selenocysteine incorporation in bacteria, our knowledge about the eukaryotic process, where some of the more intriguing mechanistic questions lie, has lagged behind. The focus of this proposal is to further our understanding of the process of selenocysteine incorporation in eukaryotes, through investigation of the RNA and protein factors mediating this process, and their interactions. This includes continuing structural studies of the RNA sequences that direct selenocysteine incorporation, and intriguingly, some recently identified polymorphisms in these structures that appear to have consequences for human disease. We are also focusing on identification and characterization of the protein factors that interact with these RNAs to mediate incorporation at the ribosome. Finally, proposed studies include investigation of the functions and mechanisms of regulation of newly identified selenoproteins.