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Science 15 December 1995:
Vol. 270. no. 5243, pp. 1842 - 1845
DOI: 10.1126/science.270.5243.1842
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Reports

Solution Structure of a Cisplatin-Induced DNA Interstrand Cross-Link

Huifang Huang (1),  Leiming Zhu (1),  Brian R. Reid,  Gary P. Drobny (2),  Paul B. Hopkins (2)

The widely used antitumor drug cis-diamminedichloroplatinum(II) (cisplatin or cis-DDP) reacts with DNA, cross-linking two purine residues through the N7 atoms, which reside in the major groove in B-form DNA. The solution structure of the short duplex [d(CATAGCTATG)]2 cross-linked at the GC:GC site was determined by nuclear magnetic resonance (NMR). The deoxyguanosine-bridging cis-diammineplatinum(II) lies in the minor groove, and the complementary deoxycytidines are extrahelical. The double helix is locally reversed to a left-handed form, and the helix is unwound and bent toward the minor groove. These findings were independently confirmed by results from a phase-sensitive gel electrophoresis bending assay. The NMR structure differs markedly from previously proposed models but accounts for the chemical reactivity, the unwinding, and the bending of cis-DDP interstrand cross-linked DNA and may be important in the formation and repair of these cross-links in chromatin.


H. Huang, L. Zhu, G. P. Drobny, P. B. Hopkins, Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
B. R. Reid, Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA 98195, USA.
(1) These authors contributed equally to this work.
(2) To whom correspondence should be addressed.


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