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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center


Carmelo J. Rizzo, Ph.D.

Professor of Chemistry
Director of Graduate Studies
Professor of Biochemistry

Contact Information:

Vanderbilt University, Chemistry Department
7330 Stevenson Ctr
Nashville, TN 37235-1822


The research focus of the Rizzo laboratory is on DNA damage. My laboratory studies the chemical mechanism by which electrophiles react with DNA to form DNA adducts and their subsequent enzymatic processing (replication and repair).
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The research focus of the Rizzo laboratory is on DNA damage. My laboratory studies the chemical mechanism by which electrophiles react with DNA to form DNA adducts and their subsequent enzymatic processing (replication and repair). We utilize the tools to synthetic chemistry to incorporate the lesions of interest into oligonucleotides in a sequence-specific manner. We then utilize the tools of biochemistry to examine how the lesions affects replication fidelity by DNA polymerases and the recognition of the lesion by DNA repair proteins. NMR and crystallographic methods are used in collaboration with other laboratories to determine the structural perturbation caused by the lesions. The relationship between structure and DNA processing is a central theme of the research program. Current projects involve DNA lesions derived from heterocyclic aromatic amines found in cooked meats, endogenous bis-electrophiles from lipid peroxidations (acrolein and 4-hydroxynonenal) and the degradation of carbohydrates (methylglyoxal), and DNA damaging agents used in chemotherapy (methylating agents and nitrogen mustards). We have a long-standing interest in bis-electrophiles that can form interstrand DNA cross-links and DNA-protein cross-links. The Rizzo laboratory is associated with the NIEHS supported Center in Molecular Toxicology (of which Prof. Rizzo serves as Co-Deputy Director and Leader of the DNA Damage and Genetic Instability Research Core), the NCI supported Vanderbilt-Ingram Cancer Center, and the Vanderbilt Institute for Chemical Biology.

  • B.A.: Temple University (Chemistry)
  • Ph.D.: University of Pennsylvania, (Chemistry)
Research Description

Synthesis of oligonucleotides containing structurally defined carcinogen adducts: The first step of chemical carcinogenesis is the covalent modification of DNA with electrophiles. If these modifications are not repaired, they may compromise the fidelity of DNA replication leading to mutations and possibly cancer. To better understand the structure, mutagenicity and repair of such DNA-carcinogen adducts, we are developing synthetic methods for the preparation of oligonucleotides that have been modified by a carcinogen. The challenge of this work is that the carcinogen adduct must be incorporated site-specifically and in a stereochemically defined manner. We have develop an efficient route for the preparation of C8-deoxyguanosine adducts of mutagenic amines, such as those found in cooked meats. One example is the food mutagen known as IQ, which has been shown to be a potent mutagen in the Ames assay. A second class of DNA adducts we are synthesizing are those from a,b-unsaturated aldehydes which are products of lipid peroxidation. One example of such an endogenous genotoxin is 4-hydroxynonenal (4-HNE) which form exocyclic adducts with deoxyguanosine, deoxyadenosine and deoxycytidine. The reaction of 4-Hydroxynonenal with deoxyguanosine gives four stereoisomeric products. We have developed a strategy for the site-specific and stereospecific syntheses of oligonucleotides containing covalent 4-HNE adducts. This will allow us to examine the role of stereochemistry in the structure and biological activity of these adducts.

Chemical Models for Flavoenzyme Catalysis: Flavoenzymes mediate a wide variety of reaction types making them unique biological catalysts. The organic cofactors responsible for their chemical properties are derivatives of riboflavin (vitamin B2). While a tremendous body of literature now exists on flavin chemistry and biochemistry, the mechanism by which specific interactions between the cofactor and the protein environment modulate the redox and catalytic properties of riboflavin is still not fully understood. We are synthesizing chemical models that mimic specific interactions between the flavin and protein and evaluating how these interactions modulate the redox and catalytic properties of flavin cofactors. The conformation of free flavin is believed to be depended upon the oxidation state of the cofactor. We have synthesized conformationally biased flavin models and showed that the redox chemistry can be driven by conformational consideration. We have also synthesized flavin models with specific hydrogen bonds to the flavin nucleus. A growing number of flavinproteins have been identified in which the cofactors is covalently modified. In the case of some C6-modified flavin cofactors, the covalent modification appears to be an inactivation pathway. We are interested in examining the mechanism by which covalent bonds are form between the C6-position of the cofactor and the substrate during catalysis.