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

基本信息

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
项目类别：
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

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

展开

项目摘要

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.

该副本是利用资源的众多研究子项目之一由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持而且，副投影的主要研究员可能是其他来源提供的包括其他NIH来源。列出的总费用可能代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 DNA损伤反应（DDR）途径起着必不可少的肿瘤抑制作用，确保基因组信息的完整性。实际上，影响该途径成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，但在此过程中几个步骤仍然鲜为人知，这表明该途径中的关键参与者尚未确定。特别是，特征不佳的是细胞检测DNA病变的机制，这是DNA损伤响应启动的初始和关键步骤。两个主要局限性阻碍了该领域的研究：i）传统DNA损伤剂引起的DNA损伤位点的不可预测位置，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局限性：i）端粒功能障碍作为一种对特定基因组基因局诱导DNA损伤的工具，ii）一种新型技术，用于分离与特定染色质基因素相关的蛋白质，称为特定的染色质基因元素，称为分离的染色质片段的蛋白质组学（PICH）。结合了这两种方法，我将能够在定义的基因组基因座上诱导DNA损伤，以隔离和识别定位于DNA损伤位点的DNA损伤机制的成分。这种方法具有很高的创新性，并且具有鉴定哺乳动物细胞中DNA损伤途径的新成分的潜力。考虑到在癌症中发现影响该途径成分的突变的频率，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很大的意义。