Nuclear magnetic resonance solution structure of an N2-guanine DNA adduct derived from the potent tumorigen dibenzo[a, l]pyrene: Intercalation from the minor groove with ruptured Watson-Crick base pairing

Yijin Tang, Zhi Liu, Shuang Ding, Chin H. Lin, Yuqin Cai, Fabian A. Rodriguez, Jane M. Sayer, Donald M. Jerina, Shantu Amin, Suse Broyde, Nicholas E. Geacintov

Research output: Contribution to journalArticle

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-N2-dG (DB[a,l]P-dG) lesion in double-stranded DNA. In contrast to the stereochemically identical benzo[a]pyrene-derived N2-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.

Original languageEnglish (US)
Pages (from-to)9751-9762
Number of pages12
JournalBiochemistry
Volume51
Issue number48
DOIs
StatePublished - Dec 4 2012

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DNA Adducts
Epoxy Compounds
Guanine
Intercalation
Base Pairing
Magnetic Resonance Spectroscopy
Polycyclic Aromatic Hydrocarbons
Nuclear magnetic resonance
Conformations
DNA
B-Form DNA
Nucleic Acid Conformation
Estuaries
Deoxyguanosine
Enantiomers
Benzo(a)pyrene
Cytosine
Adenine
DNA Repair
Repair

ASJC Scopus subject areas

  • Biochemistry

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Nuclear magnetic resonance solution structure of an N2-guanine DNA adduct derived from the potent tumorigen dibenzo[a, l]pyrene : Intercalation from the minor groove with ruptured Watson-Crick base pairing. / Tang, Yijin; Liu, Zhi; Ding, Shuang; Lin, Chin H.; Cai, Yuqin; Rodriguez, Fabian A.; Sayer, Jane M.; Jerina, Donald M.; Amin, Shantu; Broyde, Suse; Geacintov, Nicholas E.

In: Biochemistry, Vol. 51, No. 48, 04.12.2012, p. 9751-9762.

Research output: Contribution to journalArticle

Tang, Yijin ; Liu, Zhi ; Ding, Shuang ; Lin, Chin H. ; Cai, Yuqin ; Rodriguez, Fabian A. ; Sayer, Jane M. ; Jerina, Donald M. ; Amin, Shantu ; Broyde, Suse ; Geacintov, Nicholas E. / Nuclear magnetic resonance solution structure of an N2-guanine DNA adduct derived from the potent tumorigen dibenzo[a, l]pyrene : Intercalation from the minor groove with ruptured Watson-Crick base pairing. In: Biochemistry. 2012 ; Vol. 51, No. 48. pp. 9751-9762.
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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-N2-dG (DB[a,l]P-dG) lesion in double-stranded DNA. In contrast to the stereochemically identical benzo[a]pyrene-derived N2-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.",
author = "Yijin Tang and Zhi Liu and Shuang Ding and Lin, {Chin H.} and Yuqin Cai and Rodriguez, {Fabian A.} and Sayer, {Jane M.} and Jerina, {Donald M.} and Shantu Amin and Suse Broyde and Geacintov, {Nicholas E.}",
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T1 - Nuclear magnetic resonance solution structure of an N2-guanine DNA adduct derived from the potent tumorigen dibenzo[a, l]pyrene

T2 - Intercalation from the minor groove with ruptured Watson-Crick base pairing

AU - Tang, Yijin

AU - Liu, Zhi

AU - Ding, Shuang

AU - Lin, Chin H.

AU - Cai, Yuqin

AU - Rodriguez, Fabian A.

AU - Sayer, Jane M.

AU - Jerina, Donald M.

AU - Amin, Shantu

AU - Broyde, Suse

AU - Geacintov, Nicholas E.

PY - 2012/12/4

Y1 - 2012/12/4

N2 - 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-N2-dG (DB[a,l]P-dG) lesion in double-stranded DNA. In contrast to the stereochemically identical benzo[a]pyrene-derived N2-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.

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