title: 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.
abstract: The dimensions and arrangements of aromatic rings (topology) in adducts derived from the reactions of polycyclic aromatic hydrocarbon (PAH) diol epoxide metabolites with DNA influence the distortions and stabilities of double-stranded DNA, and hence their recognition and processing by the human nucleotide excision repair (NER) system. Dibenzo[a,l]pyrene (DB[a,l]P) is a highly tumorigenic six-ring PAH, which contains a nonplanar and aromatic fjord region that is absent in the structurally related bay region five-ring PAH benzo[a]pyrene (B[a]P). The PAH diol epoxide-DNA adducts formed include the stereoisomeric 14S and 14R trans-anti-DB[a,l]P-N(2)-dG and the stereochemically analogous 10S- and 10R-B[a]P-N(2)-dG (B[a]P-dG) guanine adducts. However, nuclear magnetic resonance (NMR) solution studies of the 14S-DB[a,l]P-N(2)-dG adduct in DNA have not yet been presented. Here we have investigated the 14S-DB[a,l]P-N(2)-dG adduct in two different sequence contexts using NMR methods with distance-restrained molecular dynamics simulations. In duplexes with dC opposite the adduct deleted, a well-resolved base-displaced intercalative adduct conformation can be observed. In full duplexes, in contrast to the intercalated 14R stereoisomeric adduct, the bulky DB[a,l]P residue in the 14S adduct is positioned in a greatly widened and distorted minor groove, with significant disruptions and distortions of base pairing at the lesion site and two 5'-side adjacent base pairs. These unique structural features are significantly different from those of the stereochemically analogous but smaller B[a]P-dG adduct. The greater size and different topology of the DB[a,l]P aromatic ring system lead to greater structurally destabilizing DNA distortions that are partially compensated by stabilizing DB[a,l]P-DNA van der Waals interactions, whose combined effects impact the NER response to the adduct. These structural results broaden our understanding of the structure-function relationship in NER.
authors.affiliation: Department of Chemistry, New York University , New York, New York 10003, United States.
authors.forename: Fabián A
authors.initials: FA
authors.lastname: Rodríguez
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Chin H
authors.initials: CH
authors.lastname: Lin
authors.forename: Shuang
authors.initials: S
authors.lastname: Ding
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Cai
authors.forename: Alexander
authors.initials: A
authors.lastname: Kolbanovskiy
authors.forename: Marina
authors.initials: M
authors.lastname: Kolbanovskiy
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: D001483:Base Sequence / Q000235:genetics; D001580:Benzopyrenes / Q000737:chemistry*; D002273:Carcinogens / Q000737:chemistry*; D018360:Crystallography, X-Ray; D018736:DNA Adducts / Q000737:chemistry* / Q000235:genetics; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011487:Protein Conformation; D013237:Stereoisomerism
chemical_list: D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; D006147:Guanine; C041517:dibenzo(a,l)pyrene