INVESTIGATIONS OF CISPLATIN-DNA CROSS-LINKS ON NUCLEOSOME CORE PARTICLES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们感兴趣的是确定核小体核心颗粒上顺铂-DNA加合物的结构特征。顺铂是FDA批准的一种有效的抗癌药物，它在核DNA上形成许多不同的交联物。铂-DNA损伤会导致转录抑制，如果不修复，还会导致细胞凋亡。在真核细胞中，核DNA包装在染色质中，染色质的基本单位是核小体核心颗粒，核小体核心颗粒是一个由146个碱基对的DNA组成的蛋白质-DNA复合体，包裹在8个组蛋白的核心上。铂-DNA加合物结构在裸DNA上已被彻底研究，但关于核小体DNA上这些损伤的特征的信息很少，因为它存在于细胞中。因此，我们有兴趣确定核小体上顺铂-DNA损伤的结构特征。核小体的几种结构已经解决，并将用于比较，因此可以突出由于铂结合而导致的DNA几何结构的差异。我们的目标是利用这些信息建立详细的结构-活性关系，以帮助解释铂-DNA交联物如何抑制细胞转录。这一研究结果将为合理设计具有增强或独特抗肿瘤疗效的新型铂类抗癌化合物提供指导。

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.