Professor of Chemistry
Ph.D., University of Pennsylvania, 1990
c.j.rizzo@vanderbilt.edu

Chemistry and Biology of DNA Damage. 

Covalent modification of DNA by electrophiles is generally accepted as the initial event in chemical carcinogenesis. If these modifications are not repaired, they can compromise the fidelity of DNA replication leading to mutations and possibly cancer. To properly study the biological processing of pre-mutagenic DNA lesions, oligonucleotides containing structurally defined carcinogen adducts are required. Our laboratory develops synthetic strategies for the site-specific incorporation of nucleotides that are chemically modified by carcinogens into DNA. Once synthesized, the structure, replication and repair of the carcinogen-modified oligonucleotides are examined. Many of these studies are preformed in collaboration with other laboratories on Vanderbilt's campus and elsewhere.

One specific project includes 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 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 studying the mechanism of the DNA crosslinking reaction and the biological processing of the DNA crosslinks.

Modern mass spectrometry and NMR are integral parts 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

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 Research in Toxicology. 2009, 22 (5): 759-778.

Christov PP, Angel KC, Guengerich FP, Rizzo CJ. Replication Past the N-5-Methyl-Formamidopyrimidine Lesion of Deoxyguanosine by DNA Polymerases and an Improved Procedure for Sequence Analysis of in Vitro Bypass Products by Mass Spectrometry. Chemical Research in Toxicology. 2009, 22 (6): 1086-1095.

Minko IG, Kozekov ID, Kozekova A, Harris TA, Rizzo CJ, Lloyd RS. Mutagenic potential of DNA-peptide crosslinks mediated by acrolein-derived DNA adducts. Mutation Research-Fundamental and Molecular Mechanisms Of Mutagenesis. 2008, 637 (1-2): 161-172.

Minko IG, Harbut M, Kozekov ID, Kozekova A, Jakobs PM, Olson SB, Moses RE, Harris TM, Rizzo CJ, Lloyd RS. Role for DNA polymerase kappa in the processing of N-2-N-2-guanine interstrand cross-links. Journal of Biological Chemistry. 2008, 283 (25): 17075-17082.

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.

Dexheimer TS, Kozekova A, Rizzo CJ, Stone MP, Pommier Y. The modulation of topoisomerase I-mediated DNA cleavage and the induction of DNA-topoisomerase I crosslinks by crotonaldehyde-derived DNA adducts. Nucleic Acids Research. 2008, 36 (12): 4128-4136.

Christov PP, Kozekov ID, Rizzo CJ, Harris TM. The formamidopyrimidine derivative of 7-(2-oxoethyl)-2 '-deoxyguanosine. Chemical Research in Toxicology. 2008, 21 (9): 1777-1786.

Minko IG, Yamanaka K, Kozekov ID, Kozekova A, Indiani C, O'Donnell ME, Jiang QF, Goodman MF, Rizzo CJ, Lloyd RS. Replication Bypass of the Acrolein-Mediated Deoxyguanine DNA-Peptide Cross-Links by DNA Polymerases of the DinB Family. Chemical Research in Toxicology. 2008, 21 (10): 1983-1990.

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.

Szekely J, Rizzo CJ, Marnett LJ. Chemical properties of oxopropenyl adducts of purine and pyrimidine nucleosides and their reactivity toward amino acid cross-link formation. Journal of the American Chemical Society. 2008, 130 (7): 2195-2201.

Katya Petrova, Ravi Kumar Jalluri, Ivan D. Kozekov, and Carmelo J. Rizzo. Mechanism of 1,N²-etheno-2'-deoxyguanosine formation from epoxyaldehyde. Chemical Research in Toxicology. 2007, 20: 1685-1692.

Stover JS, Rizzo CJ. Synthesis of Oligonucleotides containing the N-2-deoxyguanosine adduct of the dietary carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline. Chemical Research in Toxicology. 2007, 20 (12): 1972-1979.

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 Enzyme(,). Biochemistry. 2007, 46(29): 8498-8516.

Elmquist CE, Wang F, Stover JS, Stone MP, Rizzo CJ. Conformational differences of the C8-deoxyguanosine adduct of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) within the NarI recognition sequence. Chemical Research in Toxicology. 2007, 20 (3): 445-454.

Cho YJ, Kozekov ID, Harris TM, Rizzo CJ, Stone MP. Stereochemistry modulates the stability of reduced interstrand cross-links arising from R- and S-alpha-CH3-gamma-OH-1,N2-propano-2'-deoxyguanosine in the 5'-CpG-3' DNA sequence. Biochemistry. 2007, 46(10): 2608-2621.

Stover JS, Ciobanu M, Cliffel DE, Rizzo CJ. Chemical and electrochemical oxidation of C8-arylamine adducts of 2'-deoxyguanosine. Journal of the American Chemical Society. 2007, 129 (7): 2074-2081.

Wang F, DeMuro NE, Elmquist CE, Stover JS, Rizzo CJ, Stone MP. Base-displaced intercalated structure of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline in the recognition sequence of the Narl restriction enzyme, a hotspot for-2 bp deletions. Journal of the American Chemical Society. 2006, 128 (31): 10085-10095.

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 Research in Toxicology. 2006, 19 (8): 1019-1029.

Choi JY, Stover JS, Angel KC, Chowdhury G, Rizzo CJ, Guengerich FP. Biochemical basis of genotoxicity of heterocyclic arylamine food mutagens - Human DNA polymerase eta selectively produces a two-base deletion in copying the N-2-guanyl adduct of 2-amino-3-methylimidazo[4,5-f] quinoline but not the C-8 adduct at the NarI G3 site. Journal of Biological Chemistry. 2006, 281 (35): 25297-25306.

Stover JS, Chowdhury G, Zang H, Guengerich FP, Rizzo CJ. Translesion synthesis past the C8- and N-2-deoxyguanosine adducts of the dietary mutagen 2-amino-3-methylimidazo[4,5-f] quinoline in the NarI recognition sequence by prokaryotic DNA polymerases. Chemical Research in Toxicology. 2006, 19 (11): 1506-1517.

Wang H, Kozekov ID, Kozekova A, Tamura PJ, Marnett LJ, Harris TM, Rizzo CJ. Site-specific synthesis of oligonucleotides containing malondialdehyde adducts of deoxyguanosine and deoxyadenosine via a postsynthetic modification strategy. Chemical Research in Toxicology. 2006, 19 (11): 1467-1474.

Otteneder MB, Knutson CG, Daniels JS, Hashim M, Crews BC, Remmel RP, Wang H, Rizzo C, Marnett LJ. In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M(1)dG. Proceeding of the National Academy Sciences, United States of America. 2006, 103: 6665-6669.

Choi JY, Zang H, Angel KC, Kozekov ID, Goodenough AK, Rizzo CJ, Guengerich FP. Translesion synthesis across 1,N2-ethenoguanine by human DNA polymerases. Chemical Research in Toxicology. 2006, 19: 879-886.

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.

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,N-2-ethenoguanine. Journal of Biological Chemistry. 2005, 280: 29750-29764.

Specialties

• Organic Chemistry
• Bioorganic Chemistry

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