This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are interested in determining the structural features of cisplatin-DNA adducts on nucleosome core particles. Cisplatin is a potent, FDA-approved anticancer drug that forms a number of different cross-links on nuclear DNA. The Pt-DNA damage causes transcription inhibition and, if left unrepaired, cellular apoptosis. In eukaryotic cells, nuclear DNA is packaged in chromatin, the basic unit of which is the nucleosome core particle, a protein-DNA complex consisting of 146 base pairs of DNA wrapped around a core of eight histone proteins. The Pt-DNA adduct structure has been thoroughly investigated on naked DNA, but little information exists regarding the features of these lesions on nucleosomal DNA, as it exists in cells. Therefore we are interested in determining the structural features of cisplatin-DNA damage on the nucleosome. Several structures of the nucleosome have been solved and will be used for comparison, so differences in DNA geometry due to platinum binding can be highlighted.
We aim to utilize this information to establish detailed structure-activity relationships to help explain how Pt-DNA cross-links work to inhibit cellular transcription. The results of this investigation will provide leads for the rational design of new platinum anticancer compounds with increased or unique efficacy in tumors.
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