The Stone Research Group
Vanderbilt Department of Chemistry
The goal of our research is to understand the chemistry and biological consequences of molecules that damage DNA. DNA damage can lead to mutations, potentially altering protein function. The somatic cell model of human cancer posits that the accumulation of mutations within cells is one factor that is involved in the initiation of human cancers. Humans are constantly exposed to DNA damaging chemicals from a variety of sources, including their environment, diet and lifestyle choices, occupations, and essential components of normal cellular metabolism. Our research is primarily funded by the United States Public Health Service, National Institutes of Health, in particular the National Cancer Institute and the National Institute of Environmental Health Sciences.We utilize the tools of biophysical chemistry and spectroscopy to study DNA that has been site-specifically modified with various mutagenic chemicals. We have ongoing research efforts examining the chemistry of aflatoxins, butadiene, and various alpha,?beta unsaturated aldehydes in DNA. Aflatoxins are mycotoxins produced by various strains of the fungus Aspergillus. These frequently contaminate grains consumed by humans, including corn, wheat, rice, and barley. They also contaminate peanuts. Butadiene is one of the major chemical starting materials for a variety of plastics and rubber products in the chemical industry, where occupational exposure is of concern. It is also a component of diesel exhaust. A number of alpha, beta unsaturated aldehydes are produced in human cells, e.g., as byproducts of lipid peroxidation and oxidative damage. Some of these, such as acrolein and crotonaldehyde, are also components of cigarette smoke.
One method we use is NMR spectroscopy, which enables us to understand how various DNA damaging agents alter the normal structure of DNA. In an NMR experiment, samples are placed into extremely high magnetic fields, and spectroscopic transitions between nuclear spin states are monitored. The energies of these transitions are extremely sensitive to the structure and conformation of the molecule. We also utilize X-ray crystallography to examine complexes between damaged DNA and proteins that are involved in DNA processing, primarily damage-specific DNA polymerases. In an X-ray crystallography experiment, an X-ray beam diffracts a crystalline sample, allowing the positions of the heavier nuclei to be located.
The research environment at Vanderbilt University is highly interdisciplinary. Our research group has ongoing collaborations with Professor Rizzo in the Chemistry Department, and with Professors Chazin, Egli, Guengerich, and Marnett in the Biochemistry Department. We also collaborate with Professor Stephen Lloyd at the Oregon Health and Science University and Professor Barry Gold at the University of Pittsburgh.
We are located in Nashville, Tennessee, a growing metropolitan area with a population of approximately 1.5 million people, and a great city in which to live, work, and play.