Nuclear magnetic resonance studies of an N 2-guanine adduct derived from the tumorigen dibenzo[ a, l ]pyrene in DNA

Impact of adduct stereochemistry, size, and local DNA sequence on solution conformations

Fabián A. Rodríguez, Zhi Liu, Chin H. Lin, Shuang Ding, Yuqin Cai, Alexander Kolbanovskiy, Marina Kolbanovskiy, Shantu Amin, Suse Broyde, Nicholas E. Geacintov

Research output: Contribution to journalArticle

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-N2-dG and the stereochemically analogous 10S- and 10R-B[a]P-N2-dG (B[a]P-dG) guanine adducts. However, nuclear magnetic resonance (NMR) solution studies of the 14S-DB[a,l]P-N2-dG adduct in DNA have not yet been presented. Here we have investigated the 14S-DB[a,l]P-N2-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.

Original languageEnglish (US)
Pages (from-to)1827-1841
Number of pages15
JournalBiochemistry
Volume53
Issue number11
DOIs
StatePublished - Mar 25 2014

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Stereochemistry
DNA Adducts
Benzo(a)pyrene
DNA sequences
Polycyclic Aromatic Hydrocarbons
Guanine
Conformations
Magnetic Resonance Spectroscopy
Nuclear magnetic resonance
DNA Repair
DNA
Epoxy Compounds
Repair
Base Pairing
Nucleotides
Estuaries
Topology
Molecular Dynamics Simulation
Metabolites
Molecular dynamics

ASJC Scopus subject areas

  • Biochemistry

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Nuclear magnetic resonance studies of an N 2-guanine adduct derived from the tumorigen dibenzo[ a, l ]pyrene in DNA : Impact of adduct stereochemistry, size, and local DNA sequence on solution conformations. / Rodríguez, Fabián A.; Liu, Zhi; Lin, Chin H.; Ding, Shuang; Cai, Yuqin; Kolbanovskiy, Alexander; Kolbanovskiy, Marina; Amin, Shantu; Broyde, Suse; Geacintov, Nicholas E.

In: Biochemistry, Vol. 53, No. 11, 25.03.2014, p. 1827-1841.

Research output: Contribution to journalArticle

Rodríguez, Fabián A. ; Liu, Zhi ; Lin, Chin H. ; Ding, Shuang ; Cai, Yuqin ; Kolbanovskiy, Alexander ; Kolbanovskiy, Marina ; Amin, Shantu ; Broyde, Suse ; Geacintov, Nicholas E. / Nuclear magnetic resonance studies of an N 2-guanine adduct derived from the tumorigen dibenzo[ a, l ]pyrene in DNA : Impact of adduct stereochemistry, size, and local DNA sequence on solution conformations. In: Biochemistry. 2014 ; Vol. 53, No. 11. pp. 1827-1841.
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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-N2-dG and the stereochemically analogous 10S- and 10R-B[a]P-N2-dG (B[a]P-dG) guanine adducts. However, nuclear magnetic resonance (NMR) solution studies of the 14S-DB[a,l]P-N2-dG adduct in DNA have not yet been presented. Here we have investigated the 14S-DB[a,l]P-N2-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.",
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AU - Rodríguez, Fabián A.

AU - Liu, Zhi

AU - Lin, Chin H.

AU - Ding, Shuang

AU - Cai, Yuqin

AU - Kolbanovskiy, Alexander

AU - Kolbanovskiy, Marina

AU - Amin, Shantu

AU - Broyde, Suse

AU - Geacintov, Nicholas E.

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N2 - 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-N2-dG and the stereochemically analogous 10S- and 10R-B[a]P-N2-dG (B[a]P-dG) guanine adducts. However, nuclear magnetic resonance (NMR) solution studies of the 14S-DB[a,l]P-N2-dG adduct in DNA have not yet been presented. Here we have investigated the 14S-DB[a,l]P-N2-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.

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