Leona Samson
Director, Center for Environmental
Health Sciences
Professor of Toxicology, and Biological
Engineering
Ellison American Cancer Society Professor
BSc 1974, Aberdeen University, Scotland
PhD 1979, University College, London University
Room 56-235
Phone: (617) 258-7813
Email: lsamson@mit.edu
Overview
Multiple genetic changes (mutations) are required for a normal cell to become a cancer cell that has lost growth control. Such mutations are induced by natural or man-made chemical and physical agents in our environment, and in addition by certain natural products of normal or abnormal cellular metabolism. These agents attack DNA (and other cellular molecules) and the resulting damage can induce mutations, kill cells and ultimately cause cancer. The Samson lab studies the various mechanisms by which cells protect against such toxic, mutagenic and carcinogenic agents; it is intuitively obvious that if the mutagenic effects of these agents can be avoided the chance that a normal cell will become a cancer cell will be greatly diminished.
The major carcinogenic agents studied in the Samson lab are alkylating agents. Alkylating agents represent an abundant class of DNA damaging agent in our environment and they are toxic, mutagenic, teratogenic and carcinogenic. In addition certain alkylating agents are used for cancer chemotherapy with the goal of killing off tumor cells but at the same time having minimal toxic and mutagenic effects on normal tissues. One in three people in the developed world will be diagnosed with cancer at some point in their lifetime, and most of these people will undergo chemotherapy; thus, vast numbers of people will be deliberately exposed to alkylating agents (and other chemotherapeutic agents). It is clearly very important for us to understand exactly how both healthy cells and tumor cells respond when exposed to these agents.
The repair of DNA damage provides tremendous protection against the mutagenic and cytotoxic effects of alkylating agents and one of our goals is to understand the biology, the biochemistry, and the genetics of the numerous DNA repair pathways that act upon DNA alkylation damage. It is important for cells to check the progression of the cell cycle until DNA repair is complete, and the integration of DNA damage and DNA repair with the activation of cell cycle checkpoints is also being studied in the Samson lab. These pathways are being explored in the yeast S.cerevisiae, transgenic and knock-out mice, cultured mouse and human cells, as well as in human populations.
Recently, upon taking a global genomic approach to studying how cells respond upon exposure to alkylating agents, the Samson lab discovered that a large number of other quite unexpected pathways contribute to preventing the toxic effects of alkylating agents, and it appears that many of these pathways play a role that is just as important as DNA repair. These pathways include many aspects of protein and RNA metabolism, and they are currently under intense scrutiny. Ultimately we seek to understand how all of these pathways integrate at the systems level to determine the biological consequences of being exposed to agents that have the potential to cause cancer.
Research Summary
Summary of Current Research
Alkylating agents represent an abundant class of chemical DNA damaging
agent in our environment and they are toxic, mutagenic, teratogenic and
carcinogenic. Since we are continuously exposed to alkylating agents,
and since certain alkylating agents are used for cancer chemotherapy,
it is important to understand exactly how cells respond when exposed to
these agents. The repair of DNA alkylation damage provides tremendous
protection against the toxic effects of these agents and our aim is to
understand the biology, the biochemistry, and the genetics of numerous
DNA repair pathways that act upon DNA alkylation damage.
Organisms separated by enormous evolutionary distances employ similar proteins to protect against DNA damage, and we know that bacteria, yeast, and human cells induce the expression of specific sets of genes in response to such damage. Our studies on the response of Escherichia coli, Saccharomyces cerevisiae and human cells to alkylating agents have become intimately intertwined. Much of our previous work was based on the findings that bacterial DNA repair functions can operate in eukaryotic cells, and vice versa, i.e., eukaryotic DNA repair functions can operate in bacterial cells. We exploited this phenomenon to clone a large number of yeast, mouse and human DNA alkylation repair genes, and we are using these cloned genes to gain a thorough understanding of how eukaryotic cells respond to alkylating agents. Moreover, we have extended our alkylation toxicity studies from the cellular level to the whole animal level. Specifically, we have: (i) produced transgenic and knock-out mice with altered DNA repair capabilities and are now measuring their susceptibility to alkylation toxicity; and (ii) transferred DNA alkylation repair genes to bone marrow cells to determine whether such gene therapy could confer a useful level of extra resistance in the bone marrow of chemotherapy patients.
Selected Publications
Sobol, R.W., Kartalou, M., Almeida, K.H., Joyce, D.F., Engelward, B.P.,
Horton, J.K., Prasad, R., Samson, L.D. and Wilson, S.H. (2003) Base excision
repair intermediates induce p53-independent cytotoxic and genotoxic responses. J. Biol. Chem., 278: 39951-39959.
Hofseth, L. J., Khan, M. A., Ambrose, M., Nikolayeva, O., Xu-Welliver, M., Kartalou, M., Hussain, S.P., Zhou, X., Mechanic, L.E., Zurer, I., Rotter, V., Samson, L.D. and Harris, C.C. (2003) The adaptive imbalance in base excision repair enzymes generates microsatellite instability in chronic inflammation. J. Clinical Investigation, 112:1887-1894.
Hickman, M.J. and Samson, L.D. (2004) Apoptotic signaling in response to a single type of DNA lesion, 06-methylguanine. Molecular Cell, 14: 105-116.
Begley, T.J., Rosenbach, A.S., Ideker, T. and Samson, L.D. (2004) Hot spots for modulating toxicity identified by genomic phenotyping and localization mapping. Molecular Cell, 16: 117–125.
Said, M.R., Begley, T.J., Oppenheim, A.V., Lauffenburger, D.A. and Samson, L.D. (2004) Global Network Analysis of Phenotypic Effects: Protein Networks and toxicity modulation in S. cerevisiae. Proc. Natl. Acad. Sci., 101 (52): 18006-18011.
The Toxicogenomics Research Consortium (2005) Standardizing global gene expression analysis between laboratories and across platforms. Nature Methods, 2(5):351-6.
Fry, R.C., Begley, T.J. and Samson, L.D. (2005) Genome-wide responses to DNA damaging agents. Annual Reviews of Microbiology, 59:357-377.
Delaney, J., Smeester, L., Wong, C., Frick, L., Taghizadeh, K., Wishnok, J., Drennan, C., Samson, L.D. and Essigmann, J. (2005) AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo. Nature Structural and Molecular Biology, 12 (10):855-860.
Sivaraman, A., Leach, J.K., Townsend, S., Iida, T., Hogan, B.J., Stolz, D.B., Fry, R., Samson, L.D., Tannenbaum, S.R. and Griffith, L.G. (2005) A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. Current Drug Metabolism, in press.
