Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin

Patricia M. Takahara*, Amy C. Rosenzweig, Christin A. Frederick, Stephen J. Lippard

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

691 Scopus citations

Abstract

THE success of cisplatin in cancer chemotherapy derives from its ability to crosslink DNA and alter the structure. Most cisplatin-DNA adducts are intrastrand d(GpG) and d(ApG) crosslinks1, which unwind and bend the duplex to facilitate the binding of proteins that contain one or more high-mobility-group (HMG) domains2. When HMG-domain proteins such as HMG1, IXR (intrastrand-crosslink recognition) protein from yeast, or human upstream-binding factor (hUBF) bind cisplatin intrastrand crosslinks, they can be diverted from their natural binding sites on the genome and shield the adducts from excision repair3-5. These activities sensitize cells to cisplatin and contribute to its cytotoxic properties. Crystallographic information about the structure of cisplatin-DNA adducts has been limited to short single-stranded deoxyoligonucleotides such ascis[Pt(NH3) 2{d(pGpG)}]6-8. Here we describe the X-ray structure at 2.6 Å resolution of a double-stranded DNA dodecamer containing this adduct. Our information provides, to our knowledge, the first crystallographic look at a platinated DNA duplex and should help the design of new platinum and other metal crosslinking antitumour drug candidates. Moreover, the structure reveals a unique fusion of A- and B-type DNA segments that could be of more general importance.

Original languageEnglish (US)
Pages (from-to)649-652
Number of pages4
JournalNature
Volume377
Issue number6550
DOIs
StatePublished - Jan 1 1995

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin'. Together they form a unique fingerprint.

Cite this