Carmelo J. Rizzo
Professor of Chemistry
Ph.D., University of Pennsylvania 1990

NIH Postdoctoral Research Associate, Columbia University 1990-1992
c.j.rizzo@vanderbilt.edu

Organic and Bioorganic Chemistry:

One specific project include the preparation of the C8-deoxyguanosine adduct of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). IQ is a member of a family of highly mutagenic heterocyclic amines found in cooked meats. We found that the C8-IQ adduct adopts different conformations depending on the sequence of the adducted oligonucleotide and we have hypothesized that this sequence-dependent conformation plays an important role in the biological processing of the lesion. This hypothesis will be tested using in vitro and in vivo systems. The adduction of IQ with DNA also gives a minor N2-adduct of deoxyguanosine, which has not been extensively studied. We have recently completed a synthesis of the N2-adduct and have incorporated it into oligonucleotides.

A second major project in our lab involves DNA adducts derived from endogneous sources such as lipid peroxidation. Examples of such reactive electrophiles include alpha,beta-unsaturated aldehydes (acrolein, crotonaldehyde, and 4-hydroxynonenal), 2,3-epoxyaldehydes and dicarbonyl species (malondialdehyde and 4-oxo-2-nonenal). Although these compounds are chemically very simple, they react with DNA in a complex and diverse manner. We recently demonstrated that alpha,beta-unsaturated aldehydes can form inter- and intra-strand DNA crosslinks, which are a very severe but largely unstudied form of DNA damage. The crosslinking chemistry is highly dependent on the stereochemistry of the DNA adduct. In collaboration with other laboratories, we are studing the mechanism of the DNA crosslinking reaction and the biological processing of the DNA crosslinks.

Modern mass spectrometry and NMR are an integral part to all of our studies on DNA damage. We have convenient and open access to superb analytical facilities on Vanderbilt campus. Our laboratory is affiliated with the Vanderbilt Center in Molecular Toxicology, Vanderbilt Institute of Chemical Biology, and the Vanderbilt-Ingram Cancer Center.

Selected Publications

Cho YJ, Kim HY, Huang H, Slutsky A, Minko IG, Wang H, Nechev LV, Kozekov ID, Kozekova A, Tamura P, Jacob J, Voehler M, Harris TM, Lloyd RS, Rizzo CJ, Stone MP. Spectroscopic characterization of interstrand carbinolamine cross-links formed in the 5'-CpG-3' sequence by the acrolein-derived gamma-OH-1,N2-propano-2'-deoxyguanosine DNA adduct. Journal of the American Chemical Society, 2005, 127: 17686-17696.

Goodenough AK, Kozekov ID, Zang H, Choi JY, Guengerich FP, Harris TM, Rizzo CJ. Site specific synthesis and polymerase bypass of oligonucleotides containing a 6-hydroxy-3,5,6,7-tetrahydro-9H-imidazo[1,2-a]purin-9-one base, an intermediate in the formation of 1,N2-etheno-2'-deoxyguanosine. Chemical Research Toxicology, 2005 18:1701-1714.

Zang H, Goodenough AK, Choi JY, Irimia A, Loukachevitch LV, Kozekov ID, Angel KC, Rizzo CJ, Egli M, Guengerich FP. DNA adduct bypass polymerization by Sulfolobus solfataricus DNA polymerase Dpo4 - Analysis and crystal structures of multiple base pair substitution and frameshift products with the adduct 1,N2-ethenoguanine. Journal of Biological Chemistry, 2005, 280: 29750-29764

Scholdberg TA, Merritt WK, Dean SM, Kowalcyzk A, Harris CM, Harris TM, Rizzo CJ, Lloyd RS, Stone MP. Structure of an oligodeoxynucleotide containing a butadiene oxide-derived N1 beta-hydroxyalkyl deoxyinosine adduct in the human N-ras Codon 61 sequence. Biochemistry, 2005, 44: 3327-3337.

Stover JS, Rizzo CJ, Synthesis of the N2-Deoxyguanosine Adduct of the Potent Dietary Mutagen IQ. Organic Letters, 2004, 6: 4985-4988.

Elmquist CE, Stover JS, Wang Z, Rizzo CJ, Site-Specific Synthesis and Properties of Oligonucleotides Containing C8-Deoxyguanosine Adducts of the Dietary Mutagen IQ. Journal of the American Chemical Society, 2004, 126: 11189-11201.

Wang, H; Marnett, LJ.; Harris, TM.; Rizzo, CJ. A Novel Synthesis of Malondialdehyde Adducts of Deoxyguanosine, Deoxyadenosine and Deoxycytidine. Chemical Research in Toxicology, 2004, 17: 144-149.

Wang H, Kozekov ID, Harris TM, Rizzo CJ, Site-Specific Synthesis and Reactivity of Oligonucleotides Containing Stereochemically Defined 1,N2-Deoxyguanosine Adducts of the Lipid Peroxidation Product trans-4-Hydroxynonenal. Journal of the American Chemical Society, 2003, 125: 5687-5700.

Kozekov ID, Nechev LV, Mosely MD, Harris CM, Rizzo CJ, Stone MP, Harris TM, DNA Interchain Cross-links Formed by Acrolein and Crotonaldehyde. Journal of the American Chemical Society, 2003, 125: 50-61.

Fernandes PH, Wang H, Rizzo, CJ and Lloyd RS, Site-Specific Mutagenicity of Stereochemically Defined 1,N2-Deoxyguanosine Adducts of 4-Hydroxynonenal in Mammalian Cells. Environmental and Molecular Mutagenesis, 2003, 42: 68-74.

Rizzo Group Homepage 
Chemistry 220: Organic Chemistry
Chemistry 223: Advanced Organic Reactions
Chemistry 224: Bioorganic Chemistry

 For more information, please contact Simon Westlake.
2003 Vanderbilt University