Michael P. Stone
DNA damage is believed to represent the initiating step in chemical carcinogenesis. Our laboratory seeks to understand how specific DNA adducts perturb DNA structure and how these structural interfere with the biological processing of DNA. One goal is to understand the basis whereby chemical modification of DNA triggers specific mutations. Some mutations, especially those occurring in proto-oncogene sequences or tumor suppressor gene sequences, play crucial roles in the process of chemical carcinogenesis. Some fundamental questions under study are:
- How do specific DNA adducts alter the three dimensional structure of DNA?
- How does adduction affect the biological processing of DNA during replication and repair?
- How do specific DNA adducts alter the three dimensional structure of primer-template complexes with damage bypass polymerases?
- What is the role of DNA sequence in modulating adduct conformation and biological processing?
Both NMR spectroscopy and X-ray crystallography play major roles in our research program. Our laboratory is affiliated with the Vanderbilt Center in Structural Biology. NMR spectroscopy is used to determine the three dimensional structures and dynamics of site-specifically adducted oligodeoxynucleotides in aqueous solution. Crystallographic approaches allow the structural determination of larger biomolecular complexes involving DNA processing enzymes.
Space-filling model of an oligodeoxynucleo-tide containing a mutagenic lesion, 1,N2 -propanodeoxyguanosine. The model was refined using experimental NOE constraints derived from 1H NMR spectroscopy.