EXCEED THE SPACE PROVIDED. The human population is exposed to a variety of environmental cancer-causing pollutants that include fossil fuel combustion products and substances in cigarette smoke. The bay region benzo[a]pyrene (B[a]P) is the best known representative of a class of potentially carcinogenic compounds, the polycyclic aromatic hydrocarbons (PAH). Like other PAH substances, B[a]P is metabolically activated to highly reactive and mutagenic B[a]P dial epoxides that react with DNA forming adducts. Inefficient DNA repair and translesion synthesis of DNA adducts catalyzed by polymerases, especially the recently discovered bypass polymerases, are key factors that determine if a buky lesion can give rise to mutations and ultimately to cancer. However, the molecular bases of these biologically important phenomena are still poorly understood. The major objectives of this project are to elucidate (1) the mechanisms by which human DNA repair enzymes recognize and excise bulky DNA adducts such as those derived from B[a]P diol epoxides, and (2) the molecular-structural factors and mechanisms involved in translesion synthesis catalyzed by representative bypass polymerases (Dpo4, pol _, and pol q) in vitro. These questions are addressed using well defined DNA sequences with site- specifically incorporated lesions derived from the binding of B[a]P diol epoxides to the exocyclic amino groups of adenine (dA) and guanine (dG) in DNA.
Specific Aim I. Determine the DNA structural factors and adcluct conformations that cause efficient or inefficient nucleoticle excision repair of stereochemically defined B[a]P-dG and B[a]P-dA lesions employing variable base sequence context as a tool to modulate the local structural properties of the DNA.
Specific Aim 2. Determine and compare the differences and mechanisms involved in the fidelity and efficiency of translesion bypass of bulky B[a]P-dG and B[a]P-dA lesions in different base sequence contexts by Y family bypass polymerases. Modern computational and modeling techniques, based on NMR structural studies, will be employed to derive insights into adduct conformational properties and specific DNA distortions in the vicinity of the adducts that serve as signals of recognition and removal of the lesions by nucleotide excision repair proteins. Molecular dynamic simulation methods will be employed to investigate base sequence and adduct stereochemistry-dependent translesion bypass with the lesions positioned in different base sequence contexts that are known to modulate translesion synthesis. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA099194-03
Application #
6834600
Study Section
Special Emphasis Panel (ZRG1-CAMP (03))
Program Officer
Okano, Paul
Project Start
2003-01-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$335,090
Indirect Cost
Name
New York University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
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Diamant, Noam; Hendel, Ayal; Vered, Ilan et al. (2012) DNA damage bypass operates in the S and G2 phases of the cell cycle and exhibits differential mutagenicity. Nucleic Acids Res 40:170-80
Mu, Hong; Kropachev, Konstantin; Wang, Lihua et al. (2012) Nucleotide excision repair of 2-acetylaminofluorene- and 2-aminofluorene-(C8)-guanine adducts: molecular dynamics simulations elucidate how lesion structure and base sequence context impact repair efficiencies. Nucleic Acids Res 40:9675-90

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