Structure of DNA modified by highly mutagenic and tumorigenic agents, and their less active analogs will be computed with our program DUPLEX, in order to define those conformational features that underlie the mutagenic and carcinogenic activity. We are especially interested in modification by polycyclic aromatic amines and hydrocarbons, with emphasis on the following issues: (1) chemical nature of the adduct, including ring size and substituent effects; (2) nature of base modified; (3) position of modification on a given base; (4) effect of neighboring base sequences. Aromatic amine adducts of highest priority are aniline (AN), 4- aminobiphenyl (ABP), 4-acetylaminobiphenyl (AABP), 2-aminofluorene (AF), 2- acetylaminofluorene (AAF) and 1-aminopyrene (AP) bound to guanine C-8, as well as ABP bound to adenine C-8. Next in priority are N-acetylbenzidine (NAB) and the cooked food mutagens Trp-P-2 and IQ, which also form adducts to guanine C-8. Among the polycyclic aromatic hydrocarbon adducts, our first priority remains the N-2 guanine adduct of the prototype highly tumorigenic (+) anti-benzo(a)pyrene 7, 8-diol-9, 10-epoxide (BPDE) and that of its much less active (-) anti analog. The N-2 guanine adducts of the highly tumorigenic (+) anti 5-methylchrysene-1, 2-diol-3, 4 epoxide, (+) 5- MCDE, and the much less active (+) 6-MCDE analog make up a similar pair of interest to us. The adenine N-6 and guanine N-2 adducts of (-) benzo(c)phenanthrene 3, 4-diol-1, 2-epoxide-2, (-)B(c)PHDE-2 which are apparently both highly mutagenic, are next in priority. Base sequences that are identified mutagenic hotspots are to be examined first. Of current interest are the CGC sequence, and sequences with purines adjacent to the modification. In single stranded or duplex trimers, we can investigate all sequence combinations surrounding the lesion to ascertain whether some conformational feature unique to a given sequence might predict a mutagenic hotspot. Both duplexes and single strands will be investigated. Our energy minimized structures are to be used as starting conformations for molecular dynamics simulations with the AMBER force field to provide for explicit solvent and salt incorporation. In addition, we have established collaborations with investigators who are using NMR techniques to study some of the modified DNAs, and are computing energy minimized structures that are within bounds of the experimental data. A number of new computational approaches are also planned including continued development of a build-up technique for prediction of modified DNA structures, molecular dynamics simulations with larger time steps, an effort to compute free energy rather than potential energy differences between conformers, and employment of a simulated annealing algorithm to diminish the multiple minimum problem. In addition, it is planned to automate and document DUPLEX, and release it to the scientific community.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028038-12
Application #
3167954
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1981-04-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
12
Fiscal Year
1992
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
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
Cai, Yuqin; Geacintov, Nicholas E; Broyde, Suse (2014) Ribonucleotides as nucleotide excision repair substrates. DNA Repair (Amst) 13:55-60

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