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Originally published In Press as doi:10.1074/jbc.M000777200 on March 16, 2000

J. Biol. Chem., Vol. 275, Issue 21, 15789-15798, May 26, 2000
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Sequence Specificity, Conformation, and Recognition by HMG1 Protein of Major DNA Interstrand Cross-links of Antitumor Dinuclear Platinum Complexes*

Jana KasparkovaDagger , Nicholas Farrell§, and Viktor BrabecDagger

From the Dagger  Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic and the § Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia 23284-2006

Interactions of high mobility group (HMG) domain proteins with DNA modified by cisplatin plays a role in mechanisms underlying its antitumor activity. A structural motif recognized by HMG domain proteins on cisplatin-modified DNA is a stable, directional bend of the helix axis. In the present work, bending induced in DNA by major adducts of a novel class of antitumor compounds, represented by the formula [{trans-PtCl(NH3)2}H2N(CH2)2-6NH2]Cl2, was investigated. The oligodeoxyribonucleotide duplexes containing various site-specific interstrand cross-links of these bifunctional dinuclear platinum drugs were purified and characterized by Maxam-Gilbert footprinting, chemical probing, and phasing assay. It was demonstrated that the cross-links of the dinuclear compounds bent the helix much less than those of cisplatin. Gel retardation assay revealed very weak recognition of DNA adducts of dinuclear complexes by HMG1 protein. Hence, the mediation of antitumor properties of dinuclear platinum complexes by HMG domain proteins is unlikely so that polynuclear platinum compounds may represent a novel class of platinum anticancer drugs acting by a different mechanism than cisplatin and its analogues. A further understanding of how polynuclear platinum compounds modify DNA and how these modifications are processed in cells should provide a rational basis for the design of new platinum drugs rather than searching for cisplatin analogues.

* This work was supported by Grants 305/99/0695 and 307/97/P029 from the Grant Agency of the Czech Republic, Grant A5004702 from the Grant Agency of the Academy of Sciences of the Czech Republic, and National Science Foundation operating grants (to N. F.). This work is funded in part through Grant ME 152 from the U.S.-Czech International Cooperation Program of the National Science Foundation and the Ministry of Education of the Czech Republic.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of an International Research Scholar's award from the Howard Hughes Medical Institute. To whom correspondence should be addressed: Inst. of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic. Tel.: 420-5-41517148; Fax: 420-5-41211293; E-mail: brabec@ibp.cz.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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