TELOMERE DYSFUNCTION: A TOOL FOR THE STUDY OF NOVEL DNA DAMAGE RESPONSE FACTORS

端粒功能障碍：研究新型 DNA 损伤反应因子的工具

• 批准号: 8365919
• 负责人: Eros Lazzerini Denchi
• 金额: $ 1.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8365919
• 关键词: Affect; Biology; Cancer Biology; Cells; Chromatin; DNA; DNA Damage; DNA lesion; Ensure; Frequencies; Functional disorder; Funding; Fungal Genome; Genome Stability; Genomics; Grant; Human; Location; Malignant Neoplasms; Mammalian Cell; Mutation; National Center for Research Resources; Pathway interactions; Play; Principal Investigator; Process; Proteins; Proteomics; Research; Research Infrastructure; Resources; Role; Site; Source; Techniques; United States National Institutes of Health; cost; innovation; novel; response; telomere; tool; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The DNA damage response (DDR) pathway plays an essential tumor suppressive role ensuring the integrity of genomic information. Indeed, mutations affecting components of this pathway are common in human cancer. Despite extensive research in the DNA damage field several steps in this process remain poorly understood suggesting that crucial players in this pathway have yet to be identified. In particular, poorly characterized is the mechanism by which cells detect DNA lesions, which is the initial and crucial step for DNA damage response initiation. Two major limitations have hindered the research in this field: i) the unpredictable location of DNA damage sites induced by conventional DNA damage-inducing agents, ii) the lack of a technique for the isolation of proteins associated with a given DNA substrate. I will overcome these limitations by taking advantage of: i) telomere dysfunction as a tool to induce DNA damage to specific genomic loci, ii) a novel technique developed to isolate protein associated with specific chromatin loci termed Proteomics of Isolated Chromatin segments (PICh). Combining these two approaches I will be able to induce DNA damage on defined genomic loci in order to isolate and identify the components of the DNA damage machinery that localize to DNA damage sites. This approach is highly innovative and has the potential of identifying novel components of the DNA damage pathway in mammalian cells. Given the frequency by which mutations affecting components of this pathway are found in cancer we anticipate that the results of our study will be of great relevance in the field of genomic stability and cancer biology.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 DNA损伤反应(DDR)通路在保证基因组信息完整性方面发挥着重要的肿瘤抑制作用。事实上，影响这一途径组成部分的突变在人类癌症中很常见。尽管在DNA损伤领域进行了广泛的研究，但这一过程中的几个步骤仍然知之甚少，这表明这一途径中的关键角色尚未确定。尤其是细胞检测DNA损伤的机制，这是启动DNA损伤反应的初始和关键步骤。两个主要的限制阻碍了这一领域的研究：i)传统的DNA损伤诱导剂引起的DNA损伤位点的不可预测的位置；ii)缺乏分离与给定DNA底物相关的蛋白质的技术。我将通过利用以下优势来克服这些限制：i)端粒功能障碍作为一种工具来诱导特定基因组座位的DNA损伤，ii)一种被称为分离染色质片段蛋白质组学(PICH)的新技术，用于分离与特定染色质座位相关的蛋白质。结合这两种方法，我将能够在确定的基因组座位上诱导DNA损伤，以便分离和鉴定定位于DNA损伤位置的DNA损伤机制的组件。这种方法具有很高的创新性，有可能在哺乳动物细胞中识别DNA损伤途径的新成分。鉴于在癌症中发现影响这一途径组成部分的突变的频率，我们预计我们的研究结果将在基因组稳定性和癌症生物学领域具有重要意义。