The objective of the proposed work is to determine the distortion imposed on DNA by the covalent linkage of polycyclic aromatic hydrocarbons and amines that are known environmental mutagens and carcinogens. The initiation of cancer is believed to occur by covalent binding of these chemicals to DNA, but the factors that determine whether a particular lesion will lead to cancer are not understood. It is likely that the conformation of the carcinogen-DNA adducts will determine whether or not the damage is repaired, and whether a mutation that can lead to cancer will ensue on replication. Yet, very little is currently known about the conformations of carcinogen-DNA adducts. The method to be employed is minimized semi-empirical potential energy calculations. DNA adducts that have been chemically identified will be studied, including the benz[a] pyrene and 2-acetylaminofluorene adducts. In the first stage of the calculations, a global conformation search involving about 1000 trials will be made for dinucleoside monophosphate adducts. The low energy forms obtained will then be computationally incorporated in a dodecameric duplex polymer for total energy refinement. Then, the reasonable assumption that the lesion merges into a helical structure identified by crystallographic, or fiber diffraction analysis, or predicted theoretically, will be made. This assumption is necessary because of the enormous number of conformational variables in a duplex dodecamer. The base sequences to be studied on the dimer level are dCpdG, dGpdC and dApdA, which have been identified as high reactivity loci. In the larger polymer studies the base sequences observed to be mutational hotspots or high reactivity sites will be investigated, as well as sequences observed in A, B and Z DNA crystals, and the sequence observed in the point mutation of the human bladder carcinoma oncogene. The results of this investigation on the conformational influence of a series of carcinogen-DNA adducts should reveal unifying conformational features that distinguish mutagenic and carcinogenic adducts from begin ones.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028038-05
Application #
3167949
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1981-04-01
Project End
1987-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Arts and Sciences
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Fu, Iwen; Cai, Yuqin; Geacintov, Nicholas E et al. (2017) Nucleosome Histone Tail Conformation and Dynamics: Impacts of Lysine Acetylation and a Nearby Minor Groove Benzo[a]pyrene-Derived Lesion. Biochemistry 56:1963-1973
Fu, Iwen; Cai, Yuqin; Zhang, Yingkai et al. (2016) Entrapment of a Histone Tail by a DNA Lesion in a Nucleosome Suggests the Lesion Impacts Epigenetic Marking: A Molecular Dynamics Study. Biochemistry 55:239-42
Cai, Yuqin; Kropachev, Konstantin; Terzidis, Michael A et al. (2015) Differences in the Access of Lesions to the Nucleotide Excision Repair Machinery in Nucleosomes. Biochemistry 54:4181-5
Liu, Zhi; Ding, Shuang; Kropachev, Konstantin et al. (2015) Resistance to Nucleotide Excision Repair of Bulky Guanine Adducts Opposite Abasic Sites in DNA Duplexes and Relationships between Structure and Function. PLoS One 10:e0137124
Mu, Hong; Geacintov, Nicholas E; Zhang, Yingkai et al. (2015) Recognition of Damaged DNA for Nucleotide Excision Repair: A Correlated Motion Mechanism with a Mismatched cis-syn Thymine Dimer Lesion. Biochemistry 54:5263-7
Cai, Yuqin; Geacintov, Nicholas E; Broyde, Suse (2014) Ribonucleotides as nucleotide excision repair substrates. DNA Repair (Amst) 13:55-60
Lior-Hoffmann, Lee; Ding, Shuang; Geacintov, Nicholas E et al. (2014) Structural and dynamic characterization of polymerase ?'s minor groove lesion processing reveals how adduct topology impacts fidelity. Biochemistry 53:5683-91
Rodríguez, Fabián A; Liu, Zhi; Lin, Chin H et al. (2014) Nuclear magnetic resonance studies of an N2-guanine adduct derived from the tumorigen dibenzo[a,l]pyrene in DNA: impact of adduct stereochemistry, size, and local DNA sequence on solution conformations. Biochemistry 53:1827-41
Kropachev, Konstantin; Ding, Shuang; Terzidis, Michael A et al. (2014) Structural basis for the recognition of diastereomeric 5',8-cyclo-2'-deoxypurine lesions by the human nucleotide excision repair system. Nucleic Acids Res 42:5020-32
Lee, Yuan-Cho; Cai, Yuqin; Mu, Hong et al. (2014) The relationships between XPC binding to conformationally diverse DNA adducts and their excision by the human NER system: is there a correlation? DNA Repair (Amst) 19:55-63

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