Interstrand Cross-Linking by Bizelesin Produces a Watson-Crick to Hoogsteen Base-Pairing Transition Region in d(CGTAATTACG)2

Frederick C. Seaman, Laurence Hurley

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

1H NMR analysis of the bizelesin adduct of d(CGTAATTACG)2 indicates that adenines six base pairs apart on opposite DNA strands are cross-linked, yielding two major adduct conformations differing in the central duplex region (5′AATT-3′): one (major product) contains an AT step wherein both adenines are syn-oriented and Hoogsteen base paired to thymines (5HG model); the other contains anti-oriented AT-step adenines that show no evidence of hydrogen bonding with pairing thymines (5OP model). The 5OP model consists of three conformers undergoing exchange and differing in the orientation of the AT-step thymines. Bizelesin's size, rigidity, and cross-linking properties restrict the DNA adduct's range of motion and freeze out DNA conformation(s) adopted during the cross-linking process. This most reactive DNA sequence, 5′-TAATTA-3′, yields an adduct conformation (5HG) containing a stable region of Watson-Crick (WC) to Hoogsteen (HG) to Watson-Crick base-pairing transitions. While bizelesin exercises a selective effect on DNA conformation, it intrudes into regions of base stacking less than other Hoogsteen pairing-inducing drugs (e.g., echinomycin). Because of this capacity to induce stable Hoogsteen base pairing with only minimal distortion of base-base stacking, bizelesin affords an opportunity to explore this unusual DNA conformation.

Original languageEnglish (US)
Pages (from-to)12577-12585
Number of pages9
JournalBiochemistry
Volume32
Issue number47
DOIs
StatePublished - 1993
Externally publishedYes

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Nucleic Acid Conformation
Base Pairing
Thymine
Conformations
Adenine
DNA
Echinomycin
DNA Adducts
Hydrogen Bonding
Articular Range of Motion
DNA sequences
Rigidity
Hydrogen bonds
Nuclear magnetic resonance
bizelesin
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry

Cite this

Interstrand Cross-Linking by Bizelesin Produces a Watson-Crick to Hoogsteen Base-Pairing Transition Region in d(CGTAATTACG)2 . / Seaman, Frederick C.; Hurley, Laurence.

In: Biochemistry, Vol. 32, No. 47, 1993, p. 12577-12585.

Research output: Contribution to journalArticle

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abstract = "1H NMR analysis of the bizelesin adduct of d(CGTAATTACG)2 indicates that adenines six base pairs apart on opposite DNA strands are cross-linked, yielding two major adduct conformations differing in the central duplex region (5′AATT-3′): one (major product) contains an AT step wherein both adenines are syn-oriented and Hoogsteen base paired to thymines (5HG model); the other contains anti-oriented AT-step adenines that show no evidence of hydrogen bonding with pairing thymines (5OP model). The 5OP model consists of three conformers undergoing exchange and differing in the orientation of the AT-step thymines. Bizelesin's size, rigidity, and cross-linking properties restrict the DNA adduct's range of motion and freeze out DNA conformation(s) adopted during the cross-linking process. This most reactive DNA sequence, 5′-TAATTA-3′, yields an adduct conformation (5HG) containing a stable region of Watson-Crick (WC) to Hoogsteen (HG) to Watson-Crick base-pairing transitions. While bizelesin exercises a selective effect on DNA conformation, it intrudes into regions of base stacking less than other Hoogsteen pairing-inducing drugs (e.g., echinomycin). Because of this capacity to induce stable Hoogsteen base pairing with only minimal distortion of base-base stacking, bizelesin affords an opportunity to explore this unusual DNA conformation.",
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AB - 1H NMR analysis of the bizelesin adduct of d(CGTAATTACG)2 indicates that adenines six base pairs apart on opposite DNA strands are cross-linked, yielding two major adduct conformations differing in the central duplex region (5′AATT-3′): one (major product) contains an AT step wherein both adenines are syn-oriented and Hoogsteen base paired to thymines (5HG model); the other contains anti-oriented AT-step adenines that show no evidence of hydrogen bonding with pairing thymines (5OP model). The 5OP model consists of three conformers undergoing exchange and differing in the orientation of the AT-step thymines. Bizelesin's size, rigidity, and cross-linking properties restrict the DNA adduct's range of motion and freeze out DNA conformation(s) adopted during the cross-linking process. This most reactive DNA sequence, 5′-TAATTA-3′, yields an adduct conformation (5HG) containing a stable region of Watson-Crick (WC) to Hoogsteen (HG) to Watson-Crick base-pairing transitions. While bizelesin exercises a selective effect on DNA conformation, it intrudes into regions of base stacking less than other Hoogsteen pairing-inducing drugs (e.g., echinomycin). Because of this capacity to induce stable Hoogsteen base pairing with only minimal distortion of base-base stacking, bizelesin affords an opportunity to explore this unusual DNA conformation.

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