Molecular topology of polycyclic aromatic carcinogens determines DNA adduct conformation: A link to tumorigenic activity

Chin H. Lin, Xuanwei Huang, Alexander Kolbanovskii, Brian E. Hingerty, Shantu Amin, Suse Broyde, Nicholas E. Geacintov, Dinshaw J. Patel

Research output: Contribution to journalArticle

Abstract

We report below on the solution structures of stereoisomeric "fjord" region trans-anti-benzo[c]phenanthrene-N2-guanine (designated (BPh)G) adducts positioned opposite cytosine within the (C-(BPh)G-C)·(G-C-G) sequence context. We observe intercalation of the phenanthrenyl ring with stereoisomer-dependent directionality, without disruption of the modified (BPh)G·C base-pair. Intercalation occurs to the 5′ side of the modified strand for the 1S stereoisomeric adduct and to the 3′ side for the 1R stereoisomeric adduct, with the S and R-trans-isomers related to one another by inversion in a mirror plane at all four chiral carbon atoms on the benzylic ring. Intercalation of the fjord region BPh ring into the helix without disruption of the modified base-pair is achieved through buckling of the (BPh)G·C base-pair, displacement of the linkage bond from the plane of the (BPh)G base, adaptation of a chair pucker by the BPh benzylic ring and the propeller-like deviation from planarity of the BPh phenanthrenyl ring. It is noteworthy that intercalation without base-pair disruption occurs from the minor groove side for S and R-trans-anti BPh-N2-guanine adducts opposite C, in contrast to our previous demonstration of intercalation without modified base-pair disruption from the major groove side for S and R-trans-anti BPh-N6-adenine adducts opposite T. Further, these results on fjord region 1S and 1R-trans-anti (BPh)G adducts positioned opposite C are in striking contrast to earlier research with "bay" region benzo[a]pyrene-N2-guanine (designated (BP)G) adducts positioned opposite cytosine, where 10S and 10R-trans-anti stereoisomers were positioned with opposite directionality in the minor groove without modified base-pair disruption. They also are in contrast to the 10S and 10R-cis-anti stereoisomers of (BP)G adducts opposite C, where the pyrenyl ring is intercalated into the helix with directionality, but the modified base and its partner on the opposite strand are displaced out of the helix. These results are especially significant given the known greater tumorigenic potential of fjord region compared to bay region polycyclic aromatic hydrocarbons. The tumorigenic potential has been linked to repair efficiency such that bay region adducts can be readily repaired while their fjord region counterparts are refractory to repair. Our structural results propose a link between DNA adduct conformation and repair-dependent mutagenic activity, which could ultimately translate into structure-dependent differences in tumorigenic activities. We propose that the fjord region minor groove-linked BPh-N2-guanine and major groove-linked BPh-N6-adenine adducts are refractory to repair based on our observations that the phenanthrenyl ring intercalates into the helix without modified base-pair disruption. The helix is therefore minimally perturbed and the phenanthrenyl ring is not available for recognition by the repair machinery. By contrast, the bay region BP-N2-G adducts are susceptible to repair, since the repair machinery can recognize either the pyrenyl ring positioned in the minor groove for the trans-anti groove-aligned stereoisomers, or the disrupted modified base-pair for the cis-anti base-displaced intercalated stereoisomers.

Original languageEnglish (US)
Pages (from-to)1059-1080
Number of pages22
JournalJournal of Molecular Biology
Volume306
Issue number5
DOIs
StatePublished - Mar 9 2001

Fingerprint

Nucleic Acid Conformation
DNA Adducts
Base Pairing
Estuaries
Carcinogens
Stereoisomerism
Guanine
Cytosine
Adenine
Polycyclic Aromatic Hydrocarbon Bay-Region
Benzo(a)pyrene
DNA Repair
Carbon

Keywords

  • "fjord" BPh-N-G versus "bay" BP-N-G adducts
  • "fjord" BPh-N-G versus "fjord" BPh-N-A adducts
  • BPh-N-G adducts intercalate without base-pair disruption
  • Stereoisomer-related adduct directionality.

ASJC Scopus subject areas

  • Virology

Cite this

Molecular topology of polycyclic aromatic carcinogens determines DNA adduct conformation : A link to tumorigenic activity. / Lin, Chin H.; Huang, Xuanwei; Kolbanovskii, Alexander; Hingerty, Brian E.; Amin, Shantu; Broyde, Suse; Geacintov, Nicholas E.; Patel, Dinshaw J.

In: Journal of Molecular Biology, Vol. 306, No. 5, 09.03.2001, p. 1059-1080.

Research output: Contribution to journalArticle

Lin, Chin H. ; Huang, Xuanwei ; Kolbanovskii, Alexander ; Hingerty, Brian E. ; Amin, Shantu ; Broyde, Suse ; Geacintov, Nicholas E. ; Patel, Dinshaw J. / Molecular topology of polycyclic aromatic carcinogens determines DNA adduct conformation : A link to tumorigenic activity. In: Journal of Molecular Biology. 2001 ; Vol. 306, No. 5. pp. 1059-1080.
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T1 - Molecular topology of polycyclic aromatic carcinogens determines DNA adduct conformation

T2 - A link to tumorigenic activity

AU - Lin, Chin H.

AU - Huang, Xuanwei

AU - Kolbanovskii, Alexander

AU - Hingerty, Brian E.

AU - Amin, Shantu

AU - Broyde, Suse

AU - Geacintov, Nicholas E.

AU - Patel, Dinshaw J.

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N2 - We report below on the solution structures of stereoisomeric "fjord" region trans-anti-benzo[c]phenanthrene-N2-guanine (designated (BPh)G) adducts positioned opposite cytosine within the (C-(BPh)G-C)·(G-C-G) sequence context. We observe intercalation of the phenanthrenyl ring with stereoisomer-dependent directionality, without disruption of the modified (BPh)G·C base-pair. Intercalation occurs to the 5′ side of the modified strand for the 1S stereoisomeric adduct and to the 3′ side for the 1R stereoisomeric adduct, with the S and R-trans-isomers related to one another by inversion in a mirror plane at all four chiral carbon atoms on the benzylic ring. Intercalation of the fjord region BPh ring into the helix without disruption of the modified base-pair is achieved through buckling of the (BPh)G·C base-pair, displacement of the linkage bond from the plane of the (BPh)G base, adaptation of a chair pucker by the BPh benzylic ring and the propeller-like deviation from planarity of the BPh phenanthrenyl ring. It is noteworthy that intercalation without base-pair disruption occurs from the minor groove side for S and R-trans-anti BPh-N2-guanine adducts opposite C, in contrast to our previous demonstration of intercalation without modified base-pair disruption from the major groove side for S and R-trans-anti BPh-N6-adenine adducts opposite T. Further, these results on fjord region 1S and 1R-trans-anti (BPh)G adducts positioned opposite C are in striking contrast to earlier research with "bay" region benzo[a]pyrene-N2-guanine (designated (BP)G) adducts positioned opposite cytosine, where 10S and 10R-trans-anti stereoisomers were positioned with opposite directionality in the minor groove without modified base-pair disruption. They also are in contrast to the 10S and 10R-cis-anti stereoisomers of (BP)G adducts opposite C, where the pyrenyl ring is intercalated into the helix with directionality, but the modified base and its partner on the opposite strand are displaced out of the helix. These results are especially significant given the known greater tumorigenic potential of fjord region compared to bay region polycyclic aromatic hydrocarbons. The tumorigenic potential has been linked to repair efficiency such that bay region adducts can be readily repaired while their fjord region counterparts are refractory to repair. Our structural results propose a link between DNA adduct conformation and repair-dependent mutagenic activity, which could ultimately translate into structure-dependent differences in tumorigenic activities. We propose that the fjord region minor groove-linked BPh-N2-guanine and major groove-linked BPh-N6-adenine adducts are refractory to repair based on our observations that the phenanthrenyl ring intercalates into the helix without modified base-pair disruption. The helix is therefore minimally perturbed and the phenanthrenyl ring is not available for recognition by the repair machinery. By contrast, the bay region BP-N2-G adducts are susceptible to repair, since the repair machinery can recognize either the pyrenyl ring positioned in the minor groove for the trans-anti groove-aligned stereoisomers, or the disrupted modified base-pair for the cis-anti base-displaced intercalated stereoisomers.

AB - We report below on the solution structures of stereoisomeric "fjord" region trans-anti-benzo[c]phenanthrene-N2-guanine (designated (BPh)G) adducts positioned opposite cytosine within the (C-(BPh)G-C)·(G-C-G) sequence context. We observe intercalation of the phenanthrenyl ring with stereoisomer-dependent directionality, without disruption of the modified (BPh)G·C base-pair. Intercalation occurs to the 5′ side of the modified strand for the 1S stereoisomeric adduct and to the 3′ side for the 1R stereoisomeric adduct, with the S and R-trans-isomers related to one another by inversion in a mirror plane at all four chiral carbon atoms on the benzylic ring. Intercalation of the fjord region BPh ring into the helix without disruption of the modified base-pair is achieved through buckling of the (BPh)G·C base-pair, displacement of the linkage bond from the plane of the (BPh)G base, adaptation of a chair pucker by the BPh benzylic ring and the propeller-like deviation from planarity of the BPh phenanthrenyl ring. It is noteworthy that intercalation without base-pair disruption occurs from the minor groove side for S and R-trans-anti BPh-N2-guanine adducts opposite C, in contrast to our previous demonstration of intercalation without modified base-pair disruption from the major groove side for S and R-trans-anti BPh-N6-adenine adducts opposite T. Further, these results on fjord region 1S and 1R-trans-anti (BPh)G adducts positioned opposite C are in striking contrast to earlier research with "bay" region benzo[a]pyrene-N2-guanine (designated (BP)G) adducts positioned opposite cytosine, where 10S and 10R-trans-anti stereoisomers were positioned with opposite directionality in the minor groove without modified base-pair disruption. They also are in contrast to the 10S and 10R-cis-anti stereoisomers of (BP)G adducts opposite C, where the pyrenyl ring is intercalated into the helix with directionality, but the modified base and its partner on the opposite strand are displaced out of the helix. These results are especially significant given the known greater tumorigenic potential of fjord region compared to bay region polycyclic aromatic hydrocarbons. The tumorigenic potential has been linked to repair efficiency such that bay region adducts can be readily repaired while their fjord region counterparts are refractory to repair. Our structural results propose a link between DNA adduct conformation and repair-dependent mutagenic activity, which could ultimately translate into structure-dependent differences in tumorigenic activities. We propose that the fjord region minor groove-linked BPh-N2-guanine and major groove-linked BPh-N6-adenine adducts are refractory to repair based on our observations that the phenanthrenyl ring intercalates into the helix without modified base-pair disruption. The helix is therefore minimally perturbed and the phenanthrenyl ring is not available for recognition by the repair machinery. By contrast, the bay region BP-N2-G adducts are susceptible to repair, since the repair machinery can recognize either the pyrenyl ring positioned in the minor groove for the trans-anti groove-aligned stereoisomers, or the disrupted modified base-pair for the cis-anti base-displaced intercalated stereoisomers.

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