Interstrand cross-links of cisplatin induce striking distortions in DNA

In the reaction between cellular DNA and cisplatin, different bifunctional adducts are formed including intrastrand and interstrand crosslinks. The re spective role of these lesions in the cytotoxicity of the drug is not yet e lucidated. This paper deals with the current knowledge on cisplatin interst rand cross-links and presents results on the formation, stability and struc ture of these adducts. A key step in the studies of these lesions is the re cent determination of solution and crystallographic structures of double-st randed oligonucleotides containing a unique interstrand cross-link. The DNA distortions induced by this adduct exhibit unprecedented features such as the location of the platinum residue in the minor groove, the extrusion of the cytosines of the cross-linked d(GpC). d(GpC) site, the bending of the h elix axis towards the minor groove and a large DNA unwinding. In addition t o a detailed determination of the distortions, the high resolution of the c rystal structure allowed us to locate the water molecules surrounding the a dduct. The possible implications of this structure for the chemical propert ies and the cellular processing of cisplatin interstrand cross-links are di scussed. (C) 1999 Elsevier Science Inc. All rights reserved.