title: Thermodynamic and structural factors in the removal of bulky DNA adducts by the nucleotide excision repair machinery.
abstract: The function of the human nucleotide excision repair (NER) apparatus is to remove bulky adducts from damaged DNA. In an effort to gain insights into the molecular mechanisms involved in the recognition and excision of bulky lesions, we investigated a series of site specifically modified oligonucleotides containing single, well-defined polycyclic aromatic hydrocarbon (PAH) diol epoxide-adenine adducts. Covalent adducts derived from the bay region PAH, benzo[a]pyrene, are removed by human NER enzymes in vitro. In contrast, the stereochemically analogous N(6)-dA adducts derived from the topologically different fjord region PAH, benzo[c]phenanthrene, are resistant to repair. The evasion of DNA repair may play a role in the observed higher tumorigenicity of the fjord region PAH diol epoxides. We are elucidating the structural and thermodynamic features of these adducts that may underlie their marked distinction in biologic function, employing high-resolution nuclear magnetic resonance studies, measurements of thermal stabilities of the PAH diol epoxide-modified oligonucleotide duplexes, and molecular dynamics simulations with free energy calculations. Our combined findings suggest that differences in the thermodynamic properties and thermal stabilities are associated with differences in distortions to the DNA induced by the lesions. These structural effects correlate with the differential NER susceptibilities and stem from the intrinsically distinct shapes of the fjord and bay region PAH diol epoxide-N(6)-adenine adducts.
authors.affiliation: Chemistry Department, New York University, New York, NY 10003-5180, USA. ng1@nyu.edu
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Geacintov
authors.forename: Suse
authors.initials: S
authors.lastname: Broyde
authors.forename: Tonko
authors.initials: T
authors.lastname: Buterin
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Naegeli
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Shixiang
authors.initials: S
authors.lastname: Yan
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
mesh_terms: D001483:Base Sequence; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism*; D004260:DNA Repair; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons