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| CRYSTAL-STRUCTURE OF DOUBLE-STRANDED DNA CONTAINING THE MAJOR ADDUCT OF THE ANTICANCER DRUG CISPLATIN |
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| Author(s): TAKAHARA PM, ROSENZWEIG AC, FREDERICK CA, LIPPARD SJ |
| Source: NATURE Volume: 377 Issue: 6550 Pages: 649-652 Published: OCT 19 1995 |
| Times Cited: 405 References: 27 |
| 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) crosslinks(1), which unwind and bend the duplex to facilitate the binding of proteins that contain one or more high-mobility-group (HMG) domains(2). 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 repair(3-5). 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 as Cis-[Pt(NH3)(2){d(pGpG)}](6-8). Here we describe the X-ray structure at 2.6 Angstrom 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: TAKAHARA, PM (reprint author), MIT, DEPT CHEM, CAMBRIDGE, MA 02139 USA |
Addresses:
1. HARVARD UNIV, SCH MED, DEPT BIOL CHEM & MOLEC PHARMACOL, BOSTON, MA 02115 USA |
| Publisher: MACMILLAN MAGAZINES LTD, 4 LITTLE ESSEX STREET, LONDON, ENGLAND WC2R 3LF |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: TA275 |
| ISSN: 0028-0836 |
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