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

核小体核心颗粒上顺铂-DNA 交联的研究

• 批准号: 8169250
• 负责人: Stephen J. Lippard
• 金额: $ 0.35万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169250
• 关键词: Antineoplastic Agents; Apoptosis; Base Pairing; Binding; Cells; Chromatin; Cisplatin; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Adducts; DNA Damage; Eukaryotic Cell; FDA approved; Funding; Genetic Transcription; Grant; Histones; Institution; Investigation; Left; Lesion; Nuclear; Nucleosome Core Particle; Nucleosomes; Platinum; Proteins; Research; Research Personnel; Resources; Source; Structure; Structure-Activity Relationship; United States National Institutes of Health; Work; cisplatin-DNA adduct; crosslink; design; interest; tumor; Antineoplastic Agents; Apoptosis; Base Pairing; Binding; Cells; Chromatin; Cisplatin; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Adducts; DNA Damage; Eukaryotic Cell; FDA approved; Funding; Genetic Transcription; Grant; Histones; Institution; Investigation; Left; Lesion; Nuclear; Nucleosome Core Particle; Nucleosomes; Platinum; Proteins; Research; Research Personnel; Resources; Source; Structure; Structure-Activity Relationship; United States National Institutes of Health; Work; cisplatin-DNA adduct; crosslink; design; interest; tumor

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 我们有兴趣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批准药物，在核DNA上形成许多不同的交联。 PT-DNA损伤会导致转录抑制作用，如果未修复，则会导致细胞凋亡。在真核细胞中，将核DNA包装在染色质中，其基本单元是核小体核心颗粒，核小体核心颗粒是一种蛋白质-DNA复合物，由146个碱基对DNA组成，包裹在八个组蛋白蛋白的核心周围。 PT-DNA加合物结构已经在裸DNA上进行了彻底研究，但是关于这些病变在核小体DNA上的特征的信息很少，因为它存在于细胞中。因此，我们有兴趣确定核小体对顺铂DNA损伤的结构特征。核小体的几个结构已被求解，并将用于比较，因此可以突出显示由于铂结合引起的DNA几何形状的差异。我们旨在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。这项研究的结果将为新的白金抗癌化合物的合理设计提供潜在客户，并具有肿瘤中升高或独特的功效。