Structure of the 1,4-bis(2′-deoxyadenosin-N6-yl)-2S,3S- butanediol intrastrand DNA cross-link arising from butadiene diepoxide in the human N-ras codon 61 sequence

Wen Xu, W. Keither Merritt, Lubomir V. Nechev, Thomas M. Harris, Constance M. Harris, Robert (Stephen) Lloyd, Michael P. Stone

Research output: Contribution to journalArticle

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Abstract

The 1,4-bis(2′-deoxyadenosin-N6-yl)-2S,3S-butanediol intrastrand DNA cross-link arises from the bis-alkylation of tandem N 6-dA sites in DNA by R,R-butadiene diepoxide (BDO2). The oligodeoxynucleotide 5′-d(C1G2G3A 4C5X6Y7G8A 9A10G11)-3′·5′-d(C 12T13T14C15T16T 17G18T19C20C21G 22)-3′ contains the BDO2 cross-link between the second and third adenines of the codon 61 sequence (underlined) of the human N-rai protooncogene and is named the (S,S)-BD-(61-2,3) cross-link (X,Y = cross-linked adenines). NMR analysis reveals that the cross-link is oriented in the major groove of duplex DNA. Watson-Crick base pairing is perturbed at base pair X6·T17, whereas base pairing is intact at base pair Y7·T16. The cross-link appears to exist in two conformations, in rapid exchange on the NMR time scale. In the first conformation, the β-OH is predicted to form a hydrogen bond with T 16 O4, whereas in the second, the β-OH is predicted to form a hydrogen bond with T17 O4. In contrast to the (R,R)-BD-(61-2,3) cross-link in the same sequence (Merritt, W. K., Nechev, L. V., Scholdberg, T. A., Dean, S. M., Kiehna, S. E., Chang, J. C., Harris, T. M., Harris, C. M., Lloyd, R. S., and Stone, M. P. (2005) Biochemistry 44, 10081-10092), the anti-conformation of the two hydroxyl groups at C β and Cγ with respect to the C β-Cγ bond results in a decreased twist between base pairs X6·T17 and Y7·T 16, and an approximate 10° bending of the duplex. These conformational differences may account for the differential mutagenicity of the (S,S)- and (R,R)-BD-(61-2,3) cross-links and suggest that stereochemistry plays a role in modulating biological responses to these cross-links (Kanuri, M., Nechev, L. V., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580).

Original languageEnglish (US)
Pages (from-to)187-198
Number of pages12
JournalChemical Research in Toxicology
Volume20
Issue number2
DOIs
StatePublished - Feb 2007

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Butylene Glycols
Codon
Base Pairing
Conformations
Adenine
DNA
Hydrogen bonds
Nuclear magnetic resonance
Biochemistry
Stereochemistry
Oligodeoxyribonucleotides
Alkylation
Hydrogen
Hydroxyl Radical
Dilatation and Curettage
erythritol anhydride

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Structure of the 1,4-bis(2′-deoxyadenosin-N6-yl)-2S,3S- butanediol intrastrand DNA cross-link arising from butadiene diepoxide in the human N-ras codon 61 sequence. / Xu, Wen; Merritt, W. Keither; Nechev, Lubomir V.; Harris, Thomas M.; Harris, Constance M.; Lloyd, Robert (Stephen); Stone, Michael P.

In: Chemical Research in Toxicology, Vol. 20, No. 2, 02.2007, p. 187-198.

Research output: Contribution to journalArticle

Xu, Wen ; Merritt, W. Keither ; Nechev, Lubomir V. ; Harris, Thomas M. ; Harris, Constance M. ; Lloyd, Robert (Stephen) ; Stone, Michael P. / Structure of the 1,4-bis(2′-deoxyadenosin-N6-yl)-2S,3S- butanediol intrastrand DNA cross-link arising from butadiene diepoxide in the human N-ras codon 61 sequence. In: Chemical Research in Toxicology. 2007 ; Vol. 20, No. 2. pp. 187-198.
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abstract = "The 1,4-bis(2′-deoxyadenosin-N6-yl)-2S,3S-butanediol intrastrand DNA cross-link arises from the bis-alkylation of tandem N 6-dA sites in DNA by R,R-butadiene diepoxide (BDO2). The oligodeoxynucleotide 5′-d(C1G2G3A 4C5X6Y7G8A 9A10G11)-3′·5′-d(C 12T13T14C15T16T 17G18T19C20C21G 22)-3′ contains the BDO2 cross-link between the second and third adenines of the codon 61 sequence (underlined) of the human N-rai protooncogene and is named the (S,S)-BD-(61-2,3) cross-link (X,Y = cross-linked adenines). NMR analysis reveals that the cross-link is oriented in the major groove of duplex DNA. Watson-Crick base pairing is perturbed at base pair X6·T17, whereas base pairing is intact at base pair Y7·T16. The cross-link appears to exist in two conformations, in rapid exchange on the NMR time scale. In the first conformation, the β-OH is predicted to form a hydrogen bond with T 16 O4, whereas in the second, the β-OH is predicted to form a hydrogen bond with T17 O4. In contrast to the (R,R)-BD-(61-2,3) cross-link in the same sequence (Merritt, W. K., Nechev, L. V., Scholdberg, T. A., Dean, S. M., Kiehna, S. E., Chang, J. C., Harris, T. M., Harris, C. M., Lloyd, R. S., and Stone, M. P. (2005) Biochemistry 44, 10081-10092), the anti-conformation of the two hydroxyl groups at C β and Cγ with respect to the C β-Cγ bond results in a decreased twist between base pairs X6·T17 and Y7·T 16, and an approximate 10° bending of the duplex. These conformational differences may account for the differential mutagenicity of the (S,S)- and (R,R)-BD-(61-2,3) cross-links and suggest that stereochemistry plays a role in modulating biological responses to these cross-links (Kanuri, M., Nechev, L. V., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580).",
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T1 - Structure of the 1,4-bis(2′-deoxyadenosin-N6-yl)-2S,3S- butanediol intrastrand DNA cross-link arising from butadiene diepoxide in the human N-ras codon 61 sequence

AU - Xu, Wen

AU - Merritt, W. Keither

AU - Nechev, Lubomir V.

AU - Harris, Thomas M.

AU - Harris, Constance M.

AU - Lloyd, Robert (Stephen)

AU - Stone, Michael P.

PY - 2007/2

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N2 - The 1,4-bis(2′-deoxyadenosin-N6-yl)-2S,3S-butanediol intrastrand DNA cross-link arises from the bis-alkylation of tandem N 6-dA sites in DNA by R,R-butadiene diepoxide (BDO2). The oligodeoxynucleotide 5′-d(C1G2G3A 4C5X6Y7G8A 9A10G11)-3′·5′-d(C 12T13T14C15T16T 17G18T19C20C21G 22)-3′ contains the BDO2 cross-link between the second and third adenines of the codon 61 sequence (underlined) of the human N-rai protooncogene and is named the (S,S)-BD-(61-2,3) cross-link (X,Y = cross-linked adenines). NMR analysis reveals that the cross-link is oriented in the major groove of duplex DNA. Watson-Crick base pairing is perturbed at base pair X6·T17, whereas base pairing is intact at base pair Y7·T16. The cross-link appears to exist in two conformations, in rapid exchange on the NMR time scale. In the first conformation, the β-OH is predicted to form a hydrogen bond with T 16 O4, whereas in the second, the β-OH is predicted to form a hydrogen bond with T17 O4. In contrast to the (R,R)-BD-(61-2,3) cross-link in the same sequence (Merritt, W. K., Nechev, L. V., Scholdberg, T. A., Dean, S. M., Kiehna, S. E., Chang, J. C., Harris, T. M., Harris, C. M., Lloyd, R. S., and Stone, M. P. (2005) Biochemistry 44, 10081-10092), the anti-conformation of the two hydroxyl groups at C β and Cγ with respect to the C β-Cγ bond results in a decreased twist between base pairs X6·T17 and Y7·T 16, and an approximate 10° bending of the duplex. These conformational differences may account for the differential mutagenicity of the (S,S)- and (R,R)-BD-(61-2,3) cross-links and suggest that stereochemistry plays a role in modulating biological responses to these cross-links (Kanuri, M., Nechev, L. V., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580).

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