title: Nuclear magnetic resonance solution structure of an N(2)-guanine DNA adduct derived from the potent tumorigen dibenzo[a,l]pyrene: intercalation from the minor groove with ruptured Watson-Crick base pairing.
abstract: The most potent tumorigen identified among the polycyclic aromatic hydrocarbons (PAH) is the nonplanar fjord region dibenzo[a,l]pyrene (DB[a,l]P). It is metabolically activated in vivo through the widely studied diol epoxide (DE) pathway to form covalent adducts with DNA bases, predominantly guanine and adenine. The (+)-11S,12R,13R,14S DE enantiomer forms adducts via its C14 position with the exocyclic amino group of guanine. Here, we present the first nuclear magnetic resonance solution structure of a DB[a,l]P-derived adduct, the 14R-(+)-trans-anti-DB[a,l]P-N(2)-dG (DB[a,l]P-dG) lesion in double-stranded DNA. In contrast to the stereochemically identical benzo[a]pyrene-derived N(2)-dG adduct (B[a]P-dG) in which the B[a]P rings reside in the B-DNA minor groove on the 3'-side of the modifed deoxyguanosine, in the DB[a,l]P-derived adduct the DB[a,l]P rings intercalate into the duplex on the 3'-side of the modified base from the sterically crowded minor groove. Watson-Crick base pairing of the modified guanine with the partner cytosine is broken, but these bases retain some stacking with the bulky DB[a,l]P ring system. This new theme in PAH DE-DNA adduct conformation differs from (1) the classical intercalation motif in which Watson-Crick base pairing is intact at the lesion site and (2) the base-displaced intercalation motif in which the damaged base and its partner are extruded from the helix. The structural considerations that lead to the intercalated conformation of the DB[a,l]P-dG lesion in contrast to the minor groove alignment of the B[a]P-dG adduct, and the implications of the DB[a,l]P-dG conformational motif for the recognition of such DNA lesions by the human nucleotide excision repair apparatus, are discussed.
authors.affiliation: Department of Chemistry, New York University, New York, NY 10003, USA.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Tang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Shuang
authors.initials: S
authors.lastname: Ding
authors.forename: Chin H
authors.initials: CH
authors.lastname: Lin
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Cai
authors.forename: Fabian A
authors.initials: FA
authors.lastname: Rodriguez
authors.forename: Jane M
authors.initials: JM
authors.lastname: Sayer
authors.forename: Donald M
authors.initials: DM
authors.lastname: Jerina
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Suse
authors.initials: S
authors.lastname: Broyde
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Geacintov
mesh_terms: D020029:Base Pairing; D001580:Benzopyrenes / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D009690:Nucleic Acid Conformation
chemical_list: D001580:Benzopyrenes; D018736:DNA Adducts; D006147:Guanine; C041517:dibenzo(a,l)pyrene