Accomodation of S-cis-tamoxifen-N2-guanine adduct within a bent and widened DNA minor groove

Sakurako Shimotakahara, Andrey Gorin, Alexander Kolbanovskiy, Abdelali Kettani, Brian E. Hingerty, Shantu Amin, Suse Broyde, Nicholas Geacintov, Dinshaw J. Patel

Research output: Contribution to journalArticle

Abstract

The non-steroidal anti-estrogen tamoxifen [TAM] has been in clinical use over the last two decades as a potent adjunct chemotherapeutic agent for treatment of breast cancer. It has also been given prophylactically to women with a strong family history of breast cancer. However, tamoxifen treatment has also been associated with increased endometrial cancer, possibly resulting from the reaction of metabolically activated tamoxifen derivatives with cellular DNA. Such DNA adducts can be mutagenic and the activities of isomeric adducts may be conformation-dependent. We therefore investigated the high resolution NMR solution conformation of one covalent adduct (cis-isomer, S-epimer of [TAM]G) formed from the reaction of tamoxifen [TAM] to N2-of guanine in the d(C-[TAM]G-C)·d(G-C-G) sequence context at the 11-mer oligonucleotide duplex level. Our NMR results establish that the S-cis [TAM]G lesion is accomodated within a widened minor groove without disruption of the Watson-Crick [TAM]G·C and flanking Watson-Crick G·C base-pairs. The helix axis of the bound DNA oligomer is bent by about 30°and is directed away from the minor groove adduct site. The presence of such a bulky [TAM]G adduct with components of the TAM residue on both the 5'- and the 3'-side of the modified base could compromise the fidelity of the minor groove polymerase scanning machinery. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)375-391
Number of pages17
JournalJournal of Molecular Biology
Volume302
Issue number2
DOIs
StatePublished - Sep 15 2000

Keywords

  • Covalent tamoxifen complex
  • Groove binding
  • Localized helical perturbation
  • Widened minor groove

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Accomodation of S-cis-tamoxifen-N<sup>2</sup>-guanine adduct within a bent and widened DNA minor groove'. Together they form a unique fingerprint.

  • Cite this

    Shimotakahara, S., Gorin, A., Kolbanovskiy, A., Kettani, A., Hingerty, B. E., Amin, S., Broyde, S., Geacintov, N., & Patel, D. J. (2000). Accomodation of S-cis-tamoxifen-N2-guanine adduct within a bent and widened DNA minor groove. Journal of Molecular Biology, 302(2), 375-391. https://doi.org/10.1006/jmbi.2000.4071