Home > Faculty > Carmelo J. Rizzo

Carmelo J. Rizzo

Title and Contact Information

Professor
Office: 7662 SC
Phone: (615) 322-6100
Email | Website

Education

Ph.D., University of Pennsylvania, 1990

Specialties

VICB
Organic Chemistry
Chemical Biology
Bioorganic Chemistry

In the News

Rizzo

Research

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

Banerjee S, Christov PP, Kozekova A, Rizzo CJ, Egli M, Stone MP. Replication Bypass of the trans-4-Hydroxynonenal-Derived (6S,8R,11S)-1,N-2-Deoxyguanosine DNA Adduct by the Sulfolobus solfataricus DNA Polymerase IV. Chemical Research in Toxicology. 2012, 25 (2): 422-435.

Huang H, Wang H, Kozekova A, Rizzo CJ, Stone MP. Formation of a N(2)-dG:N(2)-dG Carbinolamine DNA Cross-link by the trans-4-Hydroxynonenal-Derived (6S,8R,11S) 1,N(2)-dG Adduct. Journal of The American Chemical Society. 2011, 133 (40): 16101-16110.

Huang H, Wang H, Voehler MW, Kozekova A, Rizzo CJ, McCullough AK, Lloyd RS, Stone MP. gamma-Hydroxy-1,N(2)-propano-2 '-deoxyguanosine DNA Adduct Conjugates the N-Terminal Amine of the KWKK Peptide via a Carbinolamine Linkage. Chemical Research in Toxicology. 2011, 24 (7): 1123-1133.

Shanmugam G, Kozekov ID, Guengerich FP, Rizzo CJ, Stone MP. 1,N(2)-Etheno-2 '-deoxyguanosine Adopts the syn Conformation about the Glycosyl Bond When Mismatched with Deoxyadenosine. Chemical Research in Toxicology. 2011, 24 (7): 1071-1079.

Petrova KV, Stec DF, Voehler M, Rizzo CJ, Jeong BS. Synthesis of the four stereoisomers of 2,3-epoxy-4-hydroxynonanal and their reactivity with deoxyguanosine. Organic Biomolecular Chemistry. 2011, 9 (6): 1960-71.

Maddukuri L, Eoff RL, Choi J-Y, Rizzo CJ, Guengerich FP, Marnett LJ. In Vitro Bypass of the Major Malondialdehyde- and Base Propenal-Derived DNA Adduct by Human Y-family DNA Polymerases kappa, iota, and Rev1. Biochemistry. 2010, 49 (38): 8415-8424.

Christov PP, Petrova KV, Shanmugam G, Kozekov ID, Kozekova A, Guengerich FP, Stone MP, Rizzo CJ. Comparison of the in Vitro Replication of the 7-(2-Oxoheptyl)4,N-2-etheno-2 '-deoxyguanosine and 1,N-2-Etheno-2 '-deoxyguanosine Lesions by Sulfolobus solfataricus P2 DNA Polymerase IV (Dpo4). Chemical Research in Toxicology. 2010, 23 (8): 1330-1341.

Huang H, Kozekov ID, Kozekova A, Rizzo CJ, McCullough AK, Lloyd RS, Stone MP. Minor Groove Orientation of the KWKK Peptide Tethered via the N-Terminal Amine to the Acrolein-Derived 1,N-2-gamma-Hydroxypropanodeoxyguanosine Lesion with a Trimethylene Linkage. Biochemistry. 2010, 49 (29): 6155-6164.

Yamanaka K, Minko IG, Takata K, Kolbanovskiy A, Kozekov ID, Wood RD, Rizzo CJ, Lloyd RS. Novel Enzymatic Function of DNA Polymerase v in Translesion DNA Synthesis Past Major Groove DNA-Peptide and DNA-DNA Cross-Links. Chemical Research in Toxicology. 2010, 23 (3): 689-695.

Maddukuri L, Eoff RL, Rizzo CJ, Guengerich FP, Marnett LJ. Translesion DNA Synthesis across the M1dG Lesion Catalyzed by Y-Family Human DNA Polymerase Kappa (kappa). Chemical Research in Toxicology. 2010, 23 (1): 271-271.

Shanmugam G, Kozekov ID, Rizzo CJ, Egli M, Stone MP. Crystal Structures of Ternary Complexes of the Y-Class Sulfolobus solfataricus DNA Polymerase Dpo4 with a Template Containing a Reduced Analog of the Acrolein-Derived Deoxyguanosine Adduct N-2-(3-Hydroxyl-propyl)-deoxyguanosine. Chemical Research in Toxicology. 2010, 23 (1): 270-270.

Liu MM, Bandaru V, Bond JP, Jaruga P, Zhao XB, Christov PP, Burrows CJ, Rizzo CJ, Dizdaroglu M, Wallace SS. The mouse ortholog of NEIL3 is a functional DNA glycosylase in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2010, 107 (11): 4925-4930.

Shanmugam G, Kozekov ID, Guengerich F, Rizzo CJ, Stone MP. Structure of the 1,N-2-Etheno-2 '-deoxyguanosine Lesion in the 3 '-G(epsilon dG)T-5 ' Sequence Opposite a One-Base Deletion. Biochemistry. 2010, 49 (12): 2615-2626.

Christov PP, Chowdhury G, Garmendia CA, Wang F, Stover JS, Elmquist CE, Kozekova A , Angel KC, Turesky RJ, Stone MP, Guengerich FP, Rizzo CJ. The C8-2 '-Deoxyguanosine Adduct of 2-Amino-3-methylimidazo[1,2-d]naphthalene, a Carbocyclic Analogue of the Potent Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline, Is a Block to Replication in Vitro. Chemical Research in Toxicology. 2010, 23 (6): 1076-1088.

Huang H, Wang H, Lloyd RS, Rizzo CJ, Stone MP. Conformational Interconversion of the trans-4-Hydroxynonenal-Derived (6S,8R,11S) 1,N-2-Deoxyguanosine Adduct When Mismatched with Deoxyadenosine in DNA. Chemical Research in Toxicology. 2009, 22 (1): 187-200.

Knutson CG, Rubinson EH, Akingbade D, Anderson CS, Stec D, Petrova KV, Kozekov ID, Guengerich FP, Rizzo CJ, Marnett LJ. Oxidation and Glycolytic Cleavage of Etheno and Propano DNA Base Adducts. Biochemistry. 2009, 48 (4): 800-809.

Zhang HD, Eoff RL, Kozekov ID, Rizzo CJ, Egli M, Guengerich FP. Versatility of Y-family Sulfolobus solfataricus DNA Polymerase Dpo4 in Translesion Synthesis Past Bulky N-2-Alkylguanine Adducts. Journal of Biological Chemistry. 2009, 284 (6): 3563-3576.

Zhang H, Eoff RL, Kozekov ID, Rizzo CJ, Egli M, Guengerich FP. Structure-Function Relationships in Miscoding by Sulfolobus solfataricus DNA Polymerase Dpo4 GUANINE N-2,N-2-DIMETHYL SUBSTITUTION PRODUCES INACTIVE AND MISCODING POLYMERASE COMPLEXES. Journal of Biological Chemistry. 2009, 284 (26): 17687-17699.

Huang H, Kim HY, Kozekov ID, Cho YJ, Wang H, Kozekova A, Harris TM, Rizzo CJ, Stone MP. Stereospecific Formation of the (R)-gamma-Hydroxytrimethylene Interstrand N-2-dG:N-2-dG Cross-Link Arising from the gamma-OH-1, N-2-Propano-2 '-deoxyguanosine Adduct in the 5 '-CpG-3 ' DNA Sequence. Journal of the American Chemical Society. 2009, 131 (24): 8416-8424.

Eoff RL, Stafford JB, Szekely J, Rizzo CJ, Egli M, Guengerich FP, Marnett LJ. Structural and Functional Analysis of Sulfolobus solfataricus Y-Family DNA Polymerase Dpo4-Catalyzed Bypass of the Malondialdehyde-Deoxyguanosine Adduct. Biochemistry. 2009, 48 (30): 7079-7088.

Ben-Yehoyada M, Wang LC, Kozekov ID, Rizzo CJ, Gottesman ME, Gautier J. Checkpoint Signaling from a Single DNA Interstrand Crosslink. Molecular Cell. 2009, 35 (5): 704-715.

Zhang HD, Bren U, Kozekov ID, Rizzo CJ, Stec DF, Guengerich FP. Steric and Electrostatic Effects at the C2 Atom Substituent Influence Replication and Miscoding of the DNA Deamination Product Deoxyxanthosine and Analogs by DNA Polymerases. Journal of Molecular Biology. 2009, 392 (2): 251-269.

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.