Selenium is an essential micronutrient fundamentally important for human health. This has become increasingly clear as new research has shown a remarkably broad range of unsuspected health benefits which can be attributed to selenium. Reported benefits range from prevention of cancer, heart disease, and muscle disorders, to the maintenance of proper immune function, and even slowing of the aging process. Many of the diverse roles for this single micronutrient in human health are due to the incorporation of selenium into proteins as selenocysteine, the 21st amino acid. Selenocysteine (Sec) is encoded in selenoprotein mRNAs by a UGA codon which in other mRNAs initiates translational termination. Redefinition of the UGA Sec codon in eukaryotes is known to require a cis-acting sequence in the 3'UTR (SECIS) and several well characterized trans-acting factors (SBP2, eEFSec, and Sec-tRNASec). A recent report by this Principal Investigator has uncovered a hitherto unknown regulatory element located within a subset of selenoprotein mRNAs. The discovery that additional decoding information is contained in the coding portion of selenoprotein mRNAs has potentially far reaching implications for the mechanism of selenocysteine insertion and the regulation of selenoprotein expression. The overall objective of this application is to further our understanding of selenoprotein biosynthesis by elucidating the role of these eukaryotic Selenocysteine codon Receding Element (SREs).
Specific Aims proposed here are: (1) to identify and characterize selenoprotein redefinition elements using a combination of phylogenetic and mutagenic analysis in vitro and in cultured cells;(2) to investigate interactions between general or tissue specific trans-acting factors and the SRE elements;(3) to investigate the effects of SREs on selenoprotein mRNA stability, and competition between release factor mediated termination and decoding at UGA codons;and, (4) to examine the role of SRE elements in redefinition of UGA and UAG codons in mRNAs which lack 3'UTR SECIS elements. A more complete understanding of selenocysteine insertion mechanisms and its role in selenoprotein expression will provide insight into diseases arising from selenoprotein dysfunction, and may ultimately facilitate the identification of individuals who could benefit from selenium supplementation.
|Fixsen, S M; Howard, Michael T (2010) Processive selenocysteine incorporation during synthesis of eukaryotic selenoproteins. J Mol Biol 399:385-96|
|Maiti, Baijayanta; Arbogast, Sandrine; Allamand, Valérie et al. (2009) A mutation in the SEPN1 selenocysteine redefinition element (SRE) reduces selenocysteine incorporation and leads to SEPN1-related myopathy. Hum Mutat 30:411-6|
|Howard, Michael T; Moyle, Mark W; Aggarwal, Gaurav et al. (2007) A recoding element that stimulates decoding of UGA codons by Sec tRNA[Ser]Sec. RNA 13:912-20|