Professors Stone and Rizzo Awarded Program Project to Study Chemical Biology of Guanine Alkylation
Professors Stone and Rizzo have been awarded a program project grant from the National Cancer Institute (NCI), a division of the National Institutes of Health. The title of the grant is "Novel Targets in Cancer Chemotherapy: Chemical Biology of Guanine Alkylation". Also involved in the research are Professors Martin Egli of the Department of Biochemistry, R. Stephen Lloyd of the Oregon Health & Science University, and Dr. Robert Turesky of the Wadsworth Institute of the New York State Department of Public Health. The research will focus on understanding the chemical biology of DNA alkylating agents such as temozolomide, thioTEPA, and nitrogen mustards, which are agents used in cancer chemotherapy. These react with DNA at the N7 position of guanine, with less abundant, but biologically active lesions forming elsewhere. A similar spectrum of DNA lesions is formed from exposures to environmental toxicants that have cancer etiologies. The imidazole portion of N7-alkylated guanines undergo base-induced ring-opening, yielding stable alkyl-formamidopyrimidine (N5-substituted-Fapy) lesions. The central hypothesis of this program project is that the role of Fapy-dG lesions in modulating genotoxic response has been overlooked and that the Fapy-dG lesions contribute substantially to the biology associated with the DNA damaging agents. A major reason why Fapy lesions have been under-studied has been an inability to prepare DNAs containing them for biological, biochemical, and structural studies. Insights gained from this research will yield fundamental and applied understanding of 1) the identities of stable alkyl-Fapy-dG adducts and their detection in cellular DNA, 2) routes of chemical synthesis for the production and characterization of adduct-containing DNAs, 3) structural understanding of how these modified DNAs not only alter the structure of DNA, but also interface with DNA repair and replication enzymes, and 4) the biological processing of these DNAs by various repair systems to limit cytotoxicity and mutagenesis, or replication bypass to promote damage tolerance and survival, while increasing mutagenesis. Cancer cells possess mechanisms to suppress the cytotoxic effects of DNA-damaging chemotherapeutic drugs that limit their effectiveness with concomitant increases in the mutational burden to all tissues. This added genomic instability is expected to select for chemoresistant cancer cells and foster secondary tumor formation. Since DNA alkylating agents comprise a significant portion of the available chemotherapeutic drugs, knowledge of the spectrum of biologically relevant DNA lesions that are created during therapy and the biological processing of these adducts is critical for the design of more effective treatments.