Selenium is an essential trace element that exerts a number of important health benefits. The nutritional requirement for this micronutrient is likely due to its function in selenoproteins, which contain selenium as selenocysteine, the 21rst amino acid. Many selenoproteins are enzymes that contain selenocysteine at their active site. In humans, the twenty-five known selenoproteins play critical roles in anti-oxidant defense, thyroid hormone metabolism, development, muscular and nervous system function, inflammation, and cancer. Selenoprotein synthesis presents a challenge to the cell as selenocysteine is encoded by UGA, which is normally read as a stop codon. There is also a hierarchy of selenoprotein expression when selenium is limiting, with some selenoproteins expressed at the expense of others. The recoding of UGA as selenocysteine requires the Selenocysteine Insertion Sequence (SECIS), a stem-loop structure in the selenoprotein mRNA. Our lab established that the SECIS acts as a platform to recruit proteins that function in UGA recoding or modulate this process in selenium deficiency. Importantly, defects in the interaction between the SECIS and a protein that we identified, SECIS-binding protein 2 (SBP2), have been linked to human diseases. In ongoing projects, we aim to elucidate the mechanism and regulation of selenocysteine incorporation by determining how ribosomes distinguish between UGA/Sec and UGA/Stop codons, how mutations in SBP2 impact the expression of the selenoproteome, and how the hierarchy of selenoprotein synthesis is regulated in selenium deficiency. Finally, we are interested in characterizing the functions of several orphan selenoproteins, which have not been well–studied.
Selenium is an essential trace element, which is often found in over the counter vitamins. Inadequate dietary intake of selenium occurs in many regions of the world. Selenium insufficiency has been associated with a wide variety of disease, including atherosclerosis, neurodegenerative diseases and cancer. The requirement for selenium in your diet is because of its role in a small but important group of proteins called the selenoproteins. There are only 25 selenoproteins in humans but they play critical roles in diverse aspects of human health, including thyroid hormone metabolism, fertility, immunity, development, and protecting cells against stress. Interestingly, selenoproteins are made by an unusual pathway, which is different from the way normal proteins are produced. Our research is focused on understanding how selenoproteins are synthesized and how pathway is affected in selenium insufficiency.
Budiman, M.E., Bubenik, J.L., Driscoll, D.M. Identification of a molecular signature for the eIF4a3:SECIS interaction. Nucleic Acids Res., 39:7730-7739, 2011.
Azevedo, M., et al. Selenoproteins-related disease in a young girl caused by nonsense mutations in the SECISBP2 gene. J. Clin. Endo. & Metab. 95:4066-4071, 2010.
Miniard, A.C., Middleton, L.M., Budiman, M.E., Gerber, C.A., Driscoll, D.M.. Nucleolin binds to a subset of selenoprotein mRNAs and regulates their expression. Nucleic Acids Res., 38: 4807-4820, 2010.
Budiman, M.E., Bubenik, J., Middleton, L.M., Gerber, C., Cash, A., Driscoll, D.M.. Eukaryotic Initiation Factor 4a3 is a selenium-regulated RNA-binding protein that selectively inhibits selenocysteine incorporation. Molecular Cell, 35: 479-489, 2009.
Latrèche, L., Jean-Jean, O., Driscoll, D.M., Chavatte, L. Novel structural determinants in human SECIS elements modulate the translational recoding of UGA as selenocysteine. Nucleic Acids Res., 37: 5868-5890, 2009.