CRYSTAL-STRUCTURE OF DOUBLE-STRANDED DNA CONTAINING THE MAJOR ADDUCT OF THE ANTICANCER DRUG CISPLATIN

THE success of cisplatin in cancer chemotherapy derives from its abili ty to crosslink DNA and alter the structure, Most cisplatin-DNA adduct s are intrastrand d(GpG) and d(ApG) crosslinks(1), which unwind and be nd the duplex to facilitate the binding of proteins that contain one o r more high-mobility-group (HMG) domains(2). When HMG-domain proteins such as HMG1, IXR (intrastrand-crosslink recognition) protein from yea st, 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 act ivities sensitize cells to cisplatin and contribute to its cytotoxic p roperties, Crystallographic information about the structure of cisplat in-DNA adducts has been limited to short single-stranded deoxyoligonuc leotides 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 do decamer containing this adduct. Our information provides, to our knowl edge, the first crystallographic look at a platinated DNA duplex and s hould help the design of new platinum and other metal crosslinking ant itumour drug candidates. Moreover, the structure reveals a unique fusi on of A- and B-type DNA segments that could be of more general importa nce.