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Donna M. Driscoll, Ph.D.Staff
Department of Cell Biology |
Area of general research interest:
Posttranscriptional regulation of gene expression
Current program:
- Translational recoding of UGA as selenocysteine, the 21st amino acid
- Regulation of selencysteine incorporation
Investigators:
- Jodi Bubenik , Ph.D., Fellow
- Michael Budiman, Ph.D., Fellow
- Ayla Cash, Student
- Tracey Ferrara, Ph.D., Fellow
- Angela Miniard, Senior Technologist
Collaborators:
- Guy M. Chisolm, Ph.D., Department of Cell Biology, Cleveland Clinic
- Laurent Chavatte, Ph.D., Unite de Biochimie Cellulaire, CNRS, Paris France
- Paul Copeland, Ph.D., Department of Molecular Genetics and Microbiology, RWJMS-UMDNJ
Brief Description:
Selenium, an essential trace element, exerts a number of important health benefits in humans. This micronutrient may also have a protective effect against atherosclerosis, viral infections, arthritis, neurodegenerative diseases, and prostate cancer. The nutritional requirement for selenium is most likely due to its function in the selenoproteins, whose synthesis is reduced when dietary selenium is limited. Selenium is incorporated into selenoproteins as selenocysteine (Sec), the 21st amino acid. Of the 26 known mammalian selenoproteins, many are enzymes containing Sec at their active site and play a variety of roles in development, thyroid hormone metabolism, and antioxidant defense.
The synthesis of selenoproteins presents a unique challenge to the cell since Sec is encoded by UGA, which is normally read as a translational stop codon. In mammals, the recoding of UGA as Sec requires the SECIS element, a stem-loop structure in the 3? untranslated region of the mRNA. Our laboratory showed that the SECIS acts as a platform to recruit two proteins, SBP2 and ribosomal protein L30, which are components of the UGA recoding machinery. There is also a hierarchy of selenoprotein expression when selenium is limited, with some selenoproteins expressed at the expense of others. We recently identified a new SECIS-binding protein that may dictate this hierarchy.
In ongoing projects, we are (1) investigating the structure, function, and regulation of SBP2 and L30; (2) purifying and cloning novel SECIS-binding proteins; and (3) determining how the hierarchy of selenoprotein expression is regulated.
Key References:
Bubenik JL, Driscoll DM. Altered RNA-binding activity underlies abnormal thyroid hormone metabolism linked to a mutation in Sec insertion sequence binding protein 2. J Biol Chem 2007; 282:34653-62.
Chavatte, L. and D.M. Driscoll. Ribosomal protein L30 is a component of the selenocysteine recoding machinery in eukaryotes. Nature Structural and Molecular Biology, 12, 408-416, 2005. *Featured in News and Views article in Nature Str. Mol. Biol., 12, 389-390, 2005.
Driscoll, D.M. and L. Chavatte. (2004) Finding needles in a haystack: In silico identification of eukaryotic selenoprotein genes. EMBO Rep ., 5:140-141.
Fletcher, J.E., Copeland, P.R., Driscoll, D.M. and A. Krol. (2001) The selenocysteine incorporation machinery: interactions between the SECIS RNA and the SECIS-binding protein SBP2. RNA , 7:1442-1453.
Copeland, P.R., Stepanik, V.A., and D.M. Driscoll. (2001) Insight into mammalian selenocysteine insertion: Domain structure and ribosome binding properties of Sec insertion sequence binding protein-2. Mol. Cell. Biol ., 21:1491-1496.
Copeland, P.R., Fletcher, J.E., Carlson, B.A., Hatfield, D.L., and D.M. Driscoll. (2000) A novel RNA-binding protein, SBP2, is required for the translation of mammalian selenoprotein mRNAs. EMBO J ., 19:306-314.