Structure of the 1,4-Bis(2'-deoxyadenosin-N(6)-yl)-2S,3S-butanediol intrastrand DNA cross-link arising from butadiene diepoxide in the human N-ras codon 61 sequence

Chem Res Toxicol. 2007 Feb;20(2):187-98. doi: 10.1021/tx060210a. Epub 2007 Jan 27.


The 1,4-bis(2'-deoxyadenosin-N(6)-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 (BDO(2)). The oligodeoxynucleotide 5'-d(C(1)G(2)G(3)A(4)C(5)X(6)Y(7)G(8)A(9)A(10)G(11))-3'.5'-d(C(12)T(13)T(14)C(15)T(16)T(17)G(18)T(19)C(20)C(21)G(22))-3' contains the BDO(2) cross-link between the second and third adenines of the codon 61 sequence (underlined) of the human N-ras 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 X(6).T(17), whereas base pairing is intact at base pair Y(7).T(16). The cross-link appears to exist in two conformations, in rapid exchange on the NMR time scale. In the first conformation, the beta-OH is predicted to form a hydrogen bond with T(16) O(4), whereas in the second, the beta-OH is predicted to form a hydrogen bond with T(17) O(4). 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(beta) and C(gamma) with respect to the C(beta)-C(gamma) bond results in a decreased twist between base pairs X(6).T(17) and Y(7).T(16), and an approximate 10 degrees 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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Butylene Glycols
  • Codon / chemistry*
  • DNA Adducts / chemistry*
  • Deoxyadenosines
  • Epoxy Compounds / chemistry*
  • Genes, ras / genetics*
  • Humans
  • Magnetic Resonance Spectroscopy / methods
  • Magnetic Resonance Spectroscopy / standards
  • Models, Molecular
  • Molecular Structure
  • Oligodeoxyribonucleotides / chemistry
  • Reference Standards
  • Sensitivity and Specificity
  • Structure-Activity Relationship


  • 1,4-bis(2'-deoxyadenosin-N(6)-yl)-2S,3S-butanediol
  • Butylene Glycols
  • Codon
  • DNA Adducts
  • Deoxyadenosines
  • Epoxy Compounds
  • Oligodeoxyribonucleotides
  • diepoxybutane