| Michael P. Stone |
Professor of Chemistry
Ph.D., University of California, Irvine, 1981
michael.p.stone@vanderbilt.edu
Stone Research Group
Biophysical Chemistry
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.
Selected Publications
Brown KL, Bren U, Stone MP, Guengerich FP. Inherent Stereospecificity in the Reaction of Aflatoxin B-1 8,9-Epoxide with Deoxyguanosine and Efficiency of DNA Catalysis. Chemical Research in Toxicology. 2009, 22 (5): 913-917.
Minko IG, Kozekov ID, Harris TA , Rizzo CJ, Lloyd RS, Stone MP. Chemistry and Biology of DNA Containing 1,N-2-Deoxyguanosine Adducts of the alpha,beta-Unsaturated Aldehydes Acrolein, Crotonaldehyde, and 4-Hydroxynonenal. Chemical Reserach in Toxicology. 2009, 22 (5): 759-778.
Stone MP, Cho YJ, Huang H, Kim HY, Kozekov ID, Kozekova A, Wang H, Minko IG, Lloyd RS, Harris TM, Rizzo CJ. Interstrand DNA cross-links induced by alpha,beta-unsaturated aldehydes derived from lipid peroxidation and environmental sources. Accounts of Chemical Research. 2008, 41 (7): 793-804.
Huang H, Wang H, Qi N, Lloyd RS, Rizzo CJ, Stone MP. The Stereochemistry of trans-4-Hydroxynonenal-Derived Exocyclic 1,N-2-2 '-Deoxyguanosine Adducts Modulates Formation of Interstrand Cross-Links in the 5 '-CpG-3 ' Sequence. Biochemistry. 2008, 47 (44): 11457-11472.
Brown, KL, Adams, T, Jasti, VP, Basu, AK, Stone, MP. Interconversion of the cis-5R,6S- and trans-5R,6R-Thymine Glycol Adducts in Duplex DNA. Journal of the American Chemical Society. 2008, 130: 10898-10906.
Shanmugam, G, Goodenough, AK, Kozekov, ID, Harris, TM, Guengerich, FP, Rizzo, CJ, Stone, MP. Structure of the 1,N2-Ethenodeoyguanosine Adduct Opposite Cytosine in Duplex DNA: Hoogsteen Base Pairing at pH 5.2. Chemical Research in Toxicology. 2008, 21: 1795-1805.
Huang, H, Wang, H, Qi, N, Lloyd, RS, Harris, TM, Rizzo, CJ, Stone, MP. Rearrangement of the (6S,8R,11S) and (6R,8S,11R) Exocyclic 1,N2-Deoxyguanosine Adducts of trans-4-Hydroxynonenal to N2-Deoxyguanosine Cyclic Hemiacetals When Placed Complementary to Cytosine in Duplex DNA. Journal of the American Chemical Society. 2008, 130: 10898-10906.
Dexheimer, TS, Rizzo, CJ, Stone, MP, Pommier, Y. The Modulation of Topoisomerase I Cleavage and the Induction of DNA-Topoisomerase I Crosslinks by Crotonaldehyde-derived DNA Adducts. Nucleic Acids Research. 2008, 36: 4128-4136.
Wang, Y, Schnetz-Boutaud, NC, Kroth, H, Yagi, H, Sayer, JM, Kumar, S, Jerina, DM, Stone, MP. 3'-Intercalation of an N2-dG 1R-trans-anti-Benzo[c]phenanthrene DNA Adduct in an Iterated (CG)3 Repeat. Chemical Research in Toxicology. 2008, 21: 1348-1358.
Wang, Y, Musser, SK, Saleh, S, Marnett, LJ, Egli M, Stone, MP. Insertion of dNTPs Opposite the 1,N2-Propanodeoxyguanosine Adduct by the Sulfolobus solfataricus P2 DNA Polymerase IV. Biochemistry. 2008, 47: 7322-7334.
Wang, F, Li, F, Ganguly, M, Marky, LA, Gold, B, Egli, M, Stone, MP. A Bridging Water Anchors the Tethered 5-(3-aminopropyl)-2¢-Deoxyuridine Amine in the DNA Major Groove Proximate to the N+2 C•G Base Pair: Implications for Formation of Interstrand 5¢-GNC-3¢ Cross-links by Nitrogen Mustards. Biochemistry. 2008, 47: 7147-7157.
Shanmugam, G, Goodenough, AK, Kozekov, ID, Harris, TM, Guengerich, FP, Rizzo, CJ, Stone, MP. Structure of the 1,N2-Ethenodeoxyguanosine Adduct in Duplex DNA at pH 8.6.. Chemical Research in Toxicology. 2007, 20: 1601-1611.
Wang F, Elmquist CE, Stover JS, Rizzo CJ, Stone MP. DNA sequence modulates the conformation of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline in the recognition sequence of the NarI restriction elnzyme. Biochemistry. 2007, 46 (29): 8498-8516.
Wang Y, Schnetz-Boutaud NC, Saleh S, Marnett LJ, Stone MP. Bulge migration of the malondialdehdye OPdG DNA adduct when placed opposite a two-base deletion in the (CpG)(3) frameshift hotspot of the Salmonella typhimurium hisD3052 gene. Chemical Research in Toxicology. 2007, 20 (8): 1200-1210.
Ganguly M, Wang F, Kaushik M, Stone MP, Marky LA, Gold B. A study of 7-deaza-2 '-deoxyguanosine-2 '-deoxycytidine base pairing in DNA. Nucleic Acids Research. 2007, 35 (18): 6181-6195.
Elmquist CE, Wang F, Stover JS, Stone MP, Rizzo CJ. Site-specific Synthesis and Conformation of Oligonucleotides Containing the C8-Deoxyguanosine Adduct of the Dietary Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) in the NarI Recognition Sequence. Chemical Research in Toxicology. 2007, 20: 445-454.
Cho Y-J, Jacob J, Voehler M, Kim H-Y, Kozekov I, Harris TM, Stone MP. Stereochemistry Modulates the Stability of Reduced Interstrand Cross-Links Arising from R- and S-a-CH3-g-OH-1,N2-Propano-2'-deoxyguanosine in the 5'-CpG-3' DNA Sequence. Biochemistry. 2007, 46: 2608-2621.
Xu W, Merritt WK, Nechev LV, Harris TM, Harris CM, Lloyd RS, Stone MP. Solution Structure of the 1,4-Bis(2'-Deoxyadenosin-N6-yl)-2S,3S-butanediol Crosslinked Adduct Arising from Butadiene Diepoxide in the Human N-ras Codon 61 Sequence. Chemical Research in Toxicology. 2007, 20: 187-198.
Brown KL, Lyer RS, Lyer LG, Deng JZ, Voehler MW, Stone MP, Harris CM, Harris TM. Unraveling the Aflatoxin-FAPY Conundrum: Structural Basis for Differential Replicative Processing of Isomeric Forms of the Formamidopyrimidine-type DNA Adduct of Aflatoxin B1. Journal of the American Chemical Society. 2006, 128: 15188-15199.
Voehler M, Collier G, Young J, Stone MP, Germann MW. Performance of Cryogenic Probes as a Function of Ionic Strength and Sample Tube Geometry. Journal of Magnetic Resonance. 2006, 183: 102-109.
Cho YJ, Wang H, Kozekov ID, Kozekova A, Kurtz AJ, Jacob J, Voehler M, Smith J, Harris TM, Rizzo CJ, Lloyd RS, Stone MP. Orientation of the crotonaldehyde-derived N-2-[3-oxo-1(S)-methyl-propyl]-dGDNA adduct hinders interstrand cross-link formation in the 5 '-CpG-3 ' sequence. Chemical Reserach in Toxicology. 2006, 19 (8): 1019-1029.
Cho YJ, Wang H, Kozekov ID, Kurtz AJ, Jacob J, Voehler M, Smith J, Harris TM, Lloyd RS, Rizzo CJ, Stone MP. Stereospecific formation of interstrand carbinolamine DNA cross-links by crotonaldehyde- and acetaldehyde-derived alpha-CH3-gamma-OH-1,N-2-propano-2 '-deoxyguanosine adducts in the 5 '-CpG-3 ' sequence. Chemical Research in Toxicology. 2006, 19 (2): 195-208.
Specialties
- VICB
- Physical Chemistry
- Biochemistry
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