Publication list via PubMed

Research in the Berry lab is focused on selenoproteins, proteins containing the essential trace element, selenium, in the form of an unusual amino acid, selenocysteine. Most selenoproteins in higher organisms function either as antioxidants or in maintaining cellular redox balance. These functions explain the long-known antioxidant properties of selenium. In all selenoproteins whose functions are known, selenocysteine serves as the catalytic center of an enzyme, and its presence is required for optimal enzyme function.

Selenocysteine, designated the 21^st amino acid, is specified in the genetic code by UGA codons, which typically serve as stop codons. The process of inserting selenocysteine into proteins is unique to this amino acid, and occurs in organisms ranging from bacteria to man. Cotranslational incorporation of selenocysteine requires a specialized tRNA with an anticodon complementary to UGA, a specialized elongation factor that recognizes this tRNA, and specific secondary structures in selenoprotein mRNAs.

Our research focuses on two major areas, the mechanism and efficiency of selenoprotein biosynthesis, and the functions of selenoproteins in health and disease.

MECHANISM AND EFFICIENCY OF SELENOPROTEIN BIOSYNTHESIS
The first area of research includes efforts towards identifying and characterizing factors involved in, and elucidating the mechanism of selenoprotein synthesis. This project extends from our initial studies on the process of selenocysteine incorporation in eukaryotes, described in two Nature papers in 1991. The second Nature paper (1) has been referred to as the groundbreaking study in the field, and was cited in a Perspectives letter in Science. Based on this work, a patent was awarded for introduction of selenocysteine into specific sites in any eukaryotic protein. A more recent major breakthrough is our identification of the factor that inserts selenocysteine into proteins, published in EMBO Reports in August 2000 (2) and highlighted in the “news and views” section of Nature in Sept. 2000. Further studies include characterization of the kinetics of RNA-protein complex formation in vivo and the hierarchy of complex formation with different selenoprotein mRNAs, published in December 2000 in the EMBO Journal (3). Our recent elucidation of distinct protein domains that either mediate or regulate protein-protein and protein-RNA interactions was published in Mol Cell in March 2003 (4).

FUNCTIONS OF SELENOPROTEINS IN HEALTH AND DISEASE
An expanding area of interest in the laboratory addresses the functions of selenoproteins in human health and disease. The antioxidant functions of selenoproteins are crucial for protecting membranes, nucleic acids and proteins from cumulative oxidative damage. This cumulative damage has been implicated in neurodegenerative and cardiovascular diseases, aging and cancer. Recent studies from other laboratories have shown that delivery of selenium to the brain for selenoprotein synthesis is crucial for normal neuronal development (reviewed in 5). Selenoprotein P functions in selenium delivery to brain, and has been shown to prolong survival of neurons in culture. Our group was the first to overexpress this protein in cell culture (6). Studies from our laboratory and others demonstrate that selenoprotein P binds heavy metals in plasma, and may function as a heavy metal antidote. Studies on protection from heavy metal and reactive oxygen species-induced apoptosis are now in progress.

In recent years, we have broadened our focus to include use of genetically amenable organisms to investigate selenoprotein synthesis, to identify new selenoproteins, and to investigate their functions. This includes studies in C. elegans (7), D. melanogaster (8), the zebrafish, D. rerio (9), and the use of yeast genetics to study interactions between protein factors. We also recently identified and characterized a novel D. melanogaster selenoprotein, termed selenoprotein H, and showed that it functions as an antioxidant in vivo (10).