Professor of Genetics
Publications | Research | Faculty
Background:
Thomas D. Fox, a Professor of Genetics, is a member of both the Graduate Field of Genetics and Development and the Graduate Field of Biochemistry, Molecular and Cell Biology. He received his B.S. degree from Cornell University in 1971 and his Ph.D. in Biochemistry and Molecular Biology from Harvard University in 1976. He received a Helen Hay Whitney Foundation Fellowship to do postdoctoral research at the Biocenter in Basel, Switzerland. Following his postdoctoral work he remained at the Biocenter as a faculty member in the Department of Biochemistry until coming to Cornell in 1981 to join the Section of Genetics and Development.
At Cornell he received a Dupont Young Faculty Award, a Research Career Development Award from the National Institutes of Health, and the State University of New York Chancellor's Award for Excellence in Teaching. He has served as a member of the National Institutes of Health Biochemistry Study Section. Dr. Fox is an Associate Editor of Molecular Biology of the Cell. He is a member of the American Academy of Microbiology, the American Society for Microbiology, American Society for Biological Chemists, the Society for the Study of Amphibians and Reptiles and the Genetics Society of America.
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The development of mitochondria involves interaction of genes and their products from both the nucleocytoplasmic and the mitochondrial genetic systems. Yeast (Saccharomyces cerevisiae) is a very favorable organism for the study of these gene interactions, since mutations in both genetic systems can be isolated and manipulated. Furthermore, genetic transformation and homologous recombination allow the replacement of wild-type by mutant, or novel, DNA sequences in both the nuclear and mitochondrial genomes.
We can express within mitochondria synthetic genes, employing the yeast mitochondrial genetic code, that specify proteins normally encoded in the nucleus. The proteins expressed from these synthetic genes provide reporters for analyzing the regulation of mitochondrial gene expression, and passenger proteins for analyzing the transport of mitochondrially translated proteins through the inner membrane. One of our synthetic mitochondrial genes encodes the Green Fluorescent Protein, allowing us to use fluorescence microscopy to observe directly mitochondrial gene expression in vivo.
The yeast mitochondrial gene expression system employs a novel, and surprisingly complex, mechanism for targeting translation of membrane proteins to the inner membrane. Translation of most, if not all, yeast mitochondrial mRNAs requires mRNA-specific activators. These activator proteins, coded in nuclear genes, are present inside mitochondria, associated with the inner membrane. Genetic analysis of functional interactions indicates that the activator proteins interact with the mitochondrially encoded 5' untranslated leaders of their target mRNAs. In addition, at least one of them interacts with mitochondrial ribosomes, suggesting that their role is to mediate the binding of ribosomes with their target mRNAs. Thus, translation of mRNAs encoding integral membrane proteins, such as cytrochrome c oxidase subunits, is tethered to the surface of the inner membrane. In addition to their targeting function, the low-abundance mRNA-specific activators appear to play a role in modulating mitochondrial gene expression in response to environmental conditions. Downstream of synthesis, mitochondrially coded proteins must be inserted into the inner membrane by an as-yet-unknown mechanism. We are seeking to identify the components of the 'export translocase' by genetic screens employing synthetic mitochondrial reporter genes.
Click here to view Dr. Fox's PubMed listings.
Williams, E.H., N. Bsat, N. Bonnefoy, C.A. Butler and T.D. Fox. 2005. Alteration of a novel dispensable mitochondrial ribosomal small subunit protein, Rsm28p, allows translation of defective COX2 mRNAs. Eukaryot. Cell 4: 337-345.
Fiori, A., X. Perez-Martinez and T.D. Fox. 2005. Overexpression of the COX2 translational activator, Pet111p, prevents translation of COX1 mRNA and cytochrome c oxidase assembly in mitochondria of Saccharomyces cerevisiae. Mol. Microbiol. 56: 1689-1704.
Williams, E.H., X. Perez-Martinez and T.D. Fox. 2004. MrpL36p, a highly diverged L31 ribosomal protein homolog with additional functional domains in Saccharomyces cerevisiae mitochondria. Genetics 167: 65-75.
Perez-Martinez, X., S.A. Broadley and T.D. Fox. 2003. Mss51p promotes mitochondrial Cox1p synthesis and interacts with newly synthesized Cox1p. EMBO J. 22:5951-5961
Demlow, C.M., and Fox, T.D. (2003). Activity of mitochondrially synthesized reporter proteins is lower than imported proteins, and is increased by lowering cAMP in glucose-grown Saccharomyces cerevisiae cells. Genetics 165, 961-974.
Fiori, A., T.L. Mason and T.D. Fox. 2003. Evidence that synthesis of the Saccharomyces cerevisiae mitochondrially-encoded ribosomal protein Var1p may be membrane localized. Eukaryot. Cell 2: 651-653.
Williams, E.H. and T.D. Fox. 2003. Antagonistic Signals within the COX2 mRNA Coding Sequence Control Its Translation in Saccharomyces cerevisiae Mitochondria. RNA 9: 419-431.
Naithani, S., Saracco, S.A., Butler, C.A. and T.D. Fox. 2003. Interactions among COX1 , COX2 and COX3 mRNA-specific translational activator proteins on the inner surface of the mitochondrial inner membrane of Saccharomyces cerevisiae. Mol. Biol. Cell 14: 324-333.
Saracco, S.A. and T.D. Fox. 2002. Cox18p is required for export of the mitochondrially encoded Saccharomyces cerevisiae Cox2p C-tail, and interacts with Pnt1p and Mss2p in the inner membrane. Mol. Biol. Cell 13: 1122-1131.
Broadley, S.A., C.M. Demlow and T.D. Fox. 2001. A peripheral mitochondrial inner membrane protein, Mss2p, required for export of the mitochondrially coded Cox2p C-tail in Saccharomyces cerevisiae . Mol. Cell. Biol. 21: 7663-7672.
Kolesnikova, O.A., Entelis, N.S., Mireau, H., Fox, T.D., Martin, R.P., and Tarassov, I.A. (2000). Suppression of mutations in mitochondrial DNA by tRNAs imported from the cytoplasm. Science 289, 1931-1933.
Highly diverged homologs of Saccharomyces cerevisiae mitochondrial mRNA-specific translational activators have orthologous functions in other budding yeasts. Genetics 154: 999-1012 (2000). With M.C. Costanzo, N. Bonnefoy, E. H. Williams and G. D. Clark-Walker.
Accumulation of mitochondrially synthesized Saccharomyces cerevisiae Cox2p and Cox3p depends on targeting information in untranslated portions of their mRNAs. EMBO J. 17: 5796-5804 1998). With M.E. Sanchirico and T.L. Mason.