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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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。顺铂是一种有效的，FDA批准的抗癌药物，在核DNA上形成许多不同的交联。Pt-DNA损伤导致转录抑制，如果不修复，则导致细胞凋亡。在真核细胞中，核DNA被包装在染色质中，其基本单位是核小体核心颗粒，一种蛋白质-DNA复合物，由146个碱基对的DNA包裹在8个组蛋白的核心周围组成。Pt-DNA加合物结构已被彻底研究裸DNA，但很少有信息存在的核小体DNA，因为它存在于细胞中的这些病变的功能。因此，我们感兴趣的是确定顺铂对核小体的DNA损伤的结构特征。核小体的几种结构已经被解决，并将用于比较，因此由于铂结合而导致的DNA几何形状的差异可以突出显示。我们的目标是利用这些信息来建立详细的结构-活性关系，以帮助解释Pt-DNA交联如何抑制细胞转录。本研究的结果将为合理设计新的铂类抗癌化合物提供线索，这些化合物在肿瘤中具有增加的或独特的功效。

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.