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 cross-links. The respective role of these lesions in the cytotoxicity of the drug is not yet elucidated. This paper deals with the current knowledge on cisplatin interstrand cross-links and presents results on the formation, stability and structure of these adducts. A key step in the studies of these lesions is the recent determination of solution and crystallographic structures of double-stranded 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 helix axis towards the minor groove and a large DNA unwinding. In addition to a detailed determination of the distortions, the high resolution of the crystal structure allowed us to locate the water molecules surrounding the adduct. The possible implications of this structure for the chemical properties and the cellular processing of cisplatin interstrand cross-links are discussed.
Malinge
J M
JM
Centre de Biophysique Moléculaire, CNRS, Orléans, France. malinge@cnrs-orleans.fr
Giraud-Panis
M J
MJ
Leng
M
M
D002945:Cisplatin / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D018736:DNA Adducts / Q000737:chemistry / Q000187:drug effects; D005260:Female; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation / Q000187:drug effects; D011247:Pregnancy
D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004247:DNA; D002945:Cisplatin