Abstract

This project will determine the conformation of specific carcinogens adducted to DNA. Adducts of styrene and of the polycyclic aromatic hydrocarbons benzo[a]pyrene, benzo[c]phenanthrene, benz[a]anthracene, and dimethylbenz[a]anthracene will be examined within the context of the human N-ras protooncogene sequences at codons 12 and 61. These sequences have been chosen because carcinogenesis induced by these compounds is correlated with adduct formation in these sequences, leading to point mutations which result in oncogene activation.
The specific aims are to investigate how adduct structure influences conformation, to determine how regioisomers of the same adduct differ in conformation, and to determine how sequence isomers of the same adduct differ in conformation. This will enable controversies regarding the conformation of polycyclic aromatic hydrocarbon adducts in DNA to be resolved. Propanoguanosine adducts will be used as models for the pyrimidopurinone adducts formed by malondialhyde which induces frameshift mutations. These will be examined in a frameshift-prone sequence derived from the hisD3052 tester strain of S. typhimurium. The mechanism of ethylene dibromide-induced mutagenesis will be studied by examination of oligodeoxynucleotides containing s-[2-(N7-guanyl)ethyl]thiol derivatives, which represent the major DNA adduct formed by this compound. This will enable adduct conformation to be compared with biologic response.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES005355-03
Application #
3777316
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Patra, Amritraj; Politica, Dustin A; Chatterjee, Arindom et al. (2016) Mechanism of Error-Free Bypass of the Environmental Carcinogen N-(2'-Deoxyguanosin-8-yl)-3-aminobenzanthrone Adduct by Human DNA Polymerase??. Chembiochem 17:2033-2037
Zd?alik, Daria; Doma?ska, Anna; Prorok, Paulina et al. (2015) Differential repair of etheno-DNA adducts by bacterial and human AlkB proteins. DNA Repair (Amst) 30:1-10
Chang, Shiou-chi; Fedeles, Bogdan I; Wu, Jie et al. (2015) Next-generation sequencing reveals the biological significance of the N(2),3-ethenoguanine lesion in vivo. Nucleic Acids Res 43:5489-500
Gruppi, Francesca; Salyard, Tracy L Johnson; Rizzo, Carmelo J (2014) Synthesis of G-N(2)-(CH2)3-N(2)-G Trimethylene DNA interstrand cross-links. Curr Protoc Nucleic Acid Chem 5:5.14.1-5.14.15
Petrova, Katya V; Millsap, Amy D; Stec, Donald F et al. (2014) Characterization of the deoxyguanosine-lysine cross-link of methylglyoxal. Chem Res Toxicol 27:1019-29
Singh, Vipender; Fedeles, Bogdan I; Li, Deyu et al. (2014) Mechanism of repair of acrolein- and malondialdehyde-derived exocyclic guanine adducts by the ?-ketoglutarate/Fe(II) dioxygenase AlkB. Chem Res Toxicol 27:1619-31
Gruppi, Francesca; Johnson Salyard, Tracy L; Rizzo, Carmelo J (2014) Synthesis of G-N2-(CH2)3-N2-G Trimethylene DNA Interstrand Cross-Links. Curr Protoc Nucleic Acid Chem 56:5.14.1-15
Christov, Plamen P; Son, Kyu-Jun; Rizzo, Carmelo J (2014) Synthesis and characterization of oligonucleotides containing a nitrogen mustard formamidopyrimidine monoadduct of deoxyguanosine. Chem Res Toxicol 27:1610-8
Minko, Irina G; Earley, Lauriel F; Larlee, Kimberly E et al. (2014) Pyrosequencing: applicability for studying DNA damage-induced mutagenesis. Environ Mol Mutagen 55:601-8
Earley, Lauriel F; Minko, Irina G; Christov, Plamen P et al. (2013) Mutagenic Spectra Arising from Replication Bypass of the 2,6-Diamino-4-hydroxy-N(5)-methyl Formamidopyrimidine Adduct in Primate Cells. Chem Res Toxicol :

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