The structure of mutagens/carcinogens are important determinants of their ability to generate efficiently DNA adducts, and their ability to induce the mutations that lead to cancer. The structures of mutagens/carcinogens in DNA can be studied by molecular modeling techniques. Progress on studies of thymine glycol, O2 alkylthymines, O4 alkylthymines, O6methylguanine, ethenocytosine, and benzo[a]pyrene are discussed. In numerous cases, molecular modeling suggests potential explanations for biochemical and genetic results. (1) A mechanism for how thymine glycol might induce T->C mutations was uncovered. (2) A sensible rationale for the more rapid incorporator of d (O2iPrThy)TP compared to d(O2MeThy)TP opposite Ade by DNA polymerase in vitro has been found. (3) It has been shown that there is no reasonable Watson/Crick-like base pairing structures to explain the high fidelity of replication of ethenocytosine, which suggests that fidelity must be due to some other factor. One attractive possibility is that DNA polymerases have a surveillance mechanism by which the assess the base being copied. (4) In vitro replication of O6MeGua by Klenow fragment has suggested that this lesion can adopt at least two conformations that are replicated differentially. Molecular modeling suggests that anti- and syn-O6MeGua are likely to be of similar energy in DNA, which suggests that they might be relevant. (5) Experimental results from my laboratory on mutagenesis by (+) -anti-B[a]PDE suggests that there are multiple conformations are possible for its adducts. Preliminary molecular modeling results show a correlation between the calculated preferred orientation of the prenyl moiety in the minor groove and the pattern of mutation. The results mentioned in points (4) and (5) both suggest that DNA adducts of mutagens/carcinogens can adopt multiple conformations in DNA with different biological endpoints. This notion will be studied by molecular modeling techniques.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA050432-04
Application #
2093765
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1989-12-01
Project End
1996-11-30
Budget Start
1994-01-01
Budget End
1994-11-30
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Arts and Sciences
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Lee, Chiu Hong; Chandani, Sushil; Loechler, Edward L (2006) Homology modeling of four Y-family, lesion-bypass DNA polymerases: the case that E. coli Pol IV and human Pol kappa are orthologs, and E. coli Pol V and human Pol eta are orthologs. J Mol Graph Model 25:87-102
Chandani, Sushil; Lee, Chiu Hong; Loechler, Edward L (2005) Free-energy perturbation methods to study structure and energetics of DNA adducts: results for the major N2-dG adduct of benzo[a]pyrene in two conformations and different sequence contexts. Chem Res Toxicol 18:1108-23
Nagalingam, Arumugam; Seo, Kwang-Young; Loechler, Edward L (2005) Mutagenesis studies of the major benzo[a]pyrene N2-dG adduct in a 5'-TG versus a 5'-UG sequence: removal of the methyl group causes a modest decrease in the [G->T/G->A] mutational ratio. Mutagenesis 20:105-10
Yin, Jun; Seo, Kwang Young; Loechler, Edward L (2004) A role for DNA polymerase V in G --> T mutations from the major benzo[a]pyrene N2-dG adduct when studied in a 5'-TGT sequence in E. coli. DNA Repair (Amst) 3:323-34
Lee, Chiu Hong; Loechler, Edward L (2003) Molecular modeling of the major benzo[a]pyrene N2-dG adduct in cases where mutagenesis results are known in double stranded DNA. Mutat Res 529:59-76
Lee, Chiu Hong; Chandani, Sushil; Loechler, Edward L (2002) Molecular modeling of four stereoisomers of the major B[a]PDE adduct (at N(2)-dG) in five cases where the structure is known from NMR studies: molecular modeling is consistent with NMR results. Chem Res Toxicol 15:1429-44
Kozack, R; Seo, K Y; Jelinsky, S A et al. (2000) Toward an understanding of the role of DNA adduct conformation in defining mutagenic mechanism based on studies of the major adduct (formed at N(2)-dG) of the potent environmental carcinogen, benzo[a]pyrene. Mutat Res 450:41-59
Kozack, R E; Shukla, R; Loechler, E L (1999) A hypothesis for what conformation of the major adduct of (+)-anti-B[a]PDE (N2-dG) causes G-->T versus G-->A mutations based upon a correlation between mutagenesis and molecular modeling results. Carcinogenesis 20:95-102
Kozack, R E; Loechler, E L (1999) Molecular modeling of the major adduct of (+)-anti-B[a]PDE (N2-dG) in the eight conformations and the five DNA sequences most relevant to base substitution mutagenesis. Carcinogenesis 20:85-94

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