M. Mitchell Smith, Ph.D.

Professor of Microbiology
Ph.D., The Johns Hopkins University

mms7r@Virginia.EDU
Voice: (434) 924-2669
FAX: (434) 982-1071

Research Interest: The Molecular Genetics of Chromosome Structure and Dynamics

My laboratory is interested in the molecular genetics of eukaryotic chromosome structure and function, including the mechanisms of gene transcription, DNA replication, recombination, and chromosome segregation. Our research focuses on the genes that encode the histone proteins which comprise the protein subunits of the nucleosome, the primary building block of the eukaryotic chromosome. Thus, the histones are critical for chromosome structure and dynamics, and their function is required at key steps in the cell division cycle. Our experiments exploit the advanced molecular genetics of the simple eukaryote Saccharomyces cerevisiae, budding yeast. Yeast provides an experimental system that is advantageous for cell biology, biochemistry, and molecular genetic studies. A powerful collection of classical genetic and molecular techniques have been developed for yeast that permit the recombinant DNA cloning and manipulation of genes in vitro and the characterization of new mutants in vivo. Currently, we are focusing on four main research questions:

The roles of the histone amino-terminal tail domains in chromatin structure and function, particularly in DNA replication and the maintenance of genome integrity.
The roles of the nucleosome in regulating gene transcription, and how histone-histone interactions function in shaping the chromatin template.
The roles of the histones in determining the structure and morphogenesis of the centromere of the chromosome.
The roles of the "SNF/SWI" complex in remodeling chromatin for transcription, and its interaction with the adenovirus E1A oncoprotein.

Selected Publications:

Megee, P. C., Morgan, B. A., Mittman, B. A., and Smith, M. M. Genetic analysis of histone H4: Essential role of lysines subject to reversible acetylation. Science 247, 841-845 (1990). [Abstract]

Megee, P. C., Morgan, B. A., and Smith, M. M. Histone H4 and the maintenance of genome integrity. Genes & Dev. 9, 1716-1727 (1995). [Abstract]

Smith, M. M., Yang, P., Santisteban, M. S., Boone, P. W., Goldstein, A. T., and Megee, P. C. A novel histone H4 mutant defective for nuclear division and mitotic chromosome transmission Mol. Cell. Biol. 16, 1017-1026 (1996). [Abstract] {Full text (pdf)]

Edmondson, D. G., Smith, M. M., and Roth, S. Y. Repression domain of the yeast global repressor Tup1 directly interacts with histones H3 and H4 chromosome transmission Genes & Dev. 10 1247-1259 (1996). [Abstract]

Miller, M. E., Cairns, B. R., Levinson, R. S., Yamamoto, K. R., Engel, D. A., and Smith, M. M. Adenovirus E1A specifcially blocks SWI/SNF-dependent transcriptional activation Mol. Cell. Biol. 16 5737-5743 (1996). [Abstract] [Full text (pdf)]

Santisteban, M. S., Arents, G., Moudrianakis, E. N., and Smith, M. M. Histone octamer function in vivo: mutations in the dimer-tetramer interfaces disrupt both gene activation and repression. EMBO J. 16 2493-2506 (1997). [Abstract]

Mymryk, J. S. and Smith, M. M. Influence of the adenovirus 5 E1A oncogene on chromatin remodelling. Biochem. Cell Biol. 75 95-101 (1997). [Abstract]

Meluh, P. B., Yang, P., Glowczewski, L., Koshland, D., and Smith, M. M. Cse4p is a component of the core centromere of Saccharomyces cerevisiae Cell 94 607-613 (1998). [Abstract]

Smith, M. M. and Santisteban, M. S. Genetic dissection of histone function Methods 15 269-281 (1998). [Abstract] [Full text]

Glowczewski, L., P. Yang, T. Kalashnikova, M.S. Santisteban, and M.M. Smith. Histone-histone interactions and centromere function. Mol. Cell. Biol. 20 5700-5711 (2000). [Abstract]

Hsu, J.-Y., Z.-W. Sun, X. Li, M. Reuben, K. Tatchell, D.K. Bishop, J.M. Grushcow, C.J. Brame, J.A. Caldwell, D.F. Hunt, R. Lin, M.M. Smith, and C.D. Allis. Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell 102 279-291 (2000). [Abstract]

Santisteban, M.S., Kalashnikova, T., and Smith, M.M. Histone H2A.Z Regulates Transcription and Is Partially Redundant with Nucleosome Remodeling Complexes Cell 103 411-422 (2000). [Abstract]

Bird, A.W, Yu, D.Y., Pray-Grant, M.G., Qui, Q., Harmon, K.E., Megee, P.C., Grant, P., Smith, M.M., and Christman, M.F. Histone H4 tail acetylation by Esa1p is required for DNA double strand break repair Nature 419 411-415 (2002). [Abstract]

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mms7r@virginia.edu