Cisplatin and related inorganic platinum complexes are known to be potent anti-cancer drugs, particularly effective against ovarian and testicular cancers. It has been demonstrated that the Pt compound binds covalently to purine nucleotides of DNA. Recent work has indicated that the Pt-modified DNA is protected from normal cellular repair mechanisms by a class of proteins, known as HMG domain proteins. The HMG protein has a DNA binding site that is specific for bends and kinks in the DNA, like those caused by platinum binding. This interaction contributes greatly to the toxicity of Pt drugs toward tumor cells. We will explore the interaction of HMG domain proteins with platinated DNA and synthetic oligonucleotides through distance-dependent NMR studies and through site-directed mutagenesis of the binding domain. The elucidation of the mode of interaction of these proteins with modified DNA provides direction for the production of new inorganic anticancer drugs that can take advantage of the binding affinity of the domain. This can also lead to the use of new anticancer therapy using both Pt chemotherapy and directed gene therapy, to produce modified protein at the site.
