Department of Medicine
Division of Genetics
New Research Building Room 435C
77 Avenue Louis Pasteur
Boston, MA 02115
Visit my lab page here.
We are interested in redox biology and genomics as applied to aging and cancer.
We are working on understanding basic mechanisms of redox regulation of cellular processes by studying reactive oxygen species and oxidoreductase functions of cellular components. Little is known how oxidant and antioxidant signals are specifically transmitted in the cell. To understand mechanisms of redox control, we need to know identities and functions of participants in the redox process. Thus, we are developing various bioinformatics approaches and carrying out genome sequencing, proteomics and functional genomics studies, which are followed with in vitro and in vivo tests of identified targets. We are particularly interested in the redox control that involves specific and stochastic oxidation of cysteine and methionine residues in proteins.
In mammals, major redox systems are dependent on the trace element selenium, which is an essential component of various redox enzymes in thioredoxin, glutathione and methionine sulfoxide reduction pathways. Selenium is present in proteins in the form of the 21st amino acid, selenocysteine, encoded by UGA codon. Selenocysteine acts as “redox supercysteine” and is used as the catalytic residue in oxidoreductases. Because UGA is also a stop signal, selenoprotein genes are typically misannotated in sequence databases. To overcome this problem, we identify these genes by genome-wide searches for structural and thermodynamic properties of specific RNA structures and independently by searches for
selenocysteine/cysteine pairs in homologous sequences. Subsequently, we characterize functions, regulation and specific targets of selenoproteins and other oxidoreductases to gain a system-wide view on selenium metabolism and redox regulation of cellular processes.
We are currently expanding our research on the basic mechanisms of aging, which we characterize by genomics, biochemistry and cell biology methods with the help of model organisms: yeast, fruit flies, naked mole rats and mice. We also characterize the methionine sulfoxide reductase system, which is a protein and metabolite repair system. We believe that aging is the consequence of the accumulation of damaged biomolecules in cells and organisms. Therefore, understanding the mechanisms by which organisms deal with damage accumulation and how these processes themselves deteriorate is crucial to the understanding of the aging process. In addition, the genetic makeup of organisms determines lifespan, and we are interested in identifying pathways and processes that are involved in this regulation.
Our lab also studies oxidoreductases involved in the quality control of protein folding in the endoplasmic reticulum. One such protein is as a candidate protein that mediates the cancer chemopreventive effect of selenium; we are characterizing its function and role in cancer prevention to identify a mechanism by which dietary selenium decreases cancer incidence. Another project involves functional characterization of thioredoxin reductases and their downstream targets. We identified one of them as thioredoxin-glutathione reductase, which is involved in male reproduction.
We hope that our studies will provide a better understanding of the role of redox control under physiological and pathophysiological conditions, particularly with regard to aging and cancer, leading to new therapeutic and disease-preventive agents.
Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R, Gladyshev VN. (2003) Characterization of mammalian selenoproteomes. Science 300, 1439-4313.
Kim HY, Gladyshev VN. (2005) Different Catalytic Mechanisms in Mammalian Selenocysteine- and Cysteine-Containing Methionine-R-Sulfoxide Reductases. PLoS Biol. 3,
Fomenko DE, Xing W, Adair BM, Thomas DJ, Gladyshev VN. (2007) High-throughput identification of catalytic redox-active cysteine residues. Science 315, 387-389.
Turanov AA, Lobanov AV, Fomenko DE, Morrison HG, Sogin ML, Klobutcher LA, Hatfield DL, Gladyshev VN. (2009) Genetic code supports targeted insertion of two amino acids by one codon. Science 323, 259-261.
Kim EB, Fang X, Fushan AA, Huang Z, Lobanov AV, Han L, Marino SM, Sun X, Turanov AA, Yang P, Yim SH, Zhao X, Kasaikina MV, Stoletzki N, Peng C, Polak P, Xiong Z, Kiezun A, Zhu Y, Chen Y, Kryukov GV, Zhang Q, Peshkin L, Yang L, Bronson RT, Buffenstein R, Wang B, Han C, Li Q, Chen L, Zhao W, Sunyaev SR, Park TJ, Zhang G, Wang J, Gladyshev VN. (2011) Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479, 223-227.
For a complete listing of publications click here.
Last Update: 7/26/2012