The Fanconi Anemia Core and D2 Complexes

Fanconi 贫血核心和 D2 复合物

• 批准号: 7440298
• 负责人: Gary M. Kupfer
• 金额: $ 36.71万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-10 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7440298
• 关键词: Accounting; Address; Affect; BRCA1 gene; Binding; Binding Proteins; Biochemical; Biochemical Pathway; Cancer Biology; Cell Cycle; Cells; Chromatin; Complex; DNA Damage; Data; FANCG gene; Fanconi anemia protein; Fanconi' s Anemia; Functional RNA; Genes; Genetic; Genome; Genomic Instability; Goals; Hereditary Disease; Higher Order Chromatin Structure; Hypersensitivity; Laboratories; Lead; Light; Link; Literature; Localized; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Outcome; Pathway interactions; Patients; Phase; Phosphorylation; Play; Post-Translational Protein Processing; Predisposition; Property; Proteins; Publishing; RNA; RNA Binding; RNA Interference; RNA-Binding Proteins; Regulation; Research; Role; Seminal; Signal Transduction; Testing; Universities; Work; base; design; gene cloning; innovation; insight; novel; nuclease; research study; response; tool

DESCRIPTION (provided by applicant): The study of rare genetic disorders of cancer susceptibility, such as Fanconi anemia (FA) have led to seminal advances in cancer biology as a whole. The hallmark of FA is genomic instability and DNA damage hypersensitivity, but the normal function of the FA pathway or mechanism leading to cancer in the affected patients remains unknown. FA is accounted for by multiple complementation groups corresponding to at least 8 cloned genes whose encoded proteins contain few functional motifs. What is known is that the FA pathway interacts with other more defined pathways involved in cellular response to DNA damage, such as ATM and BRCA1. The Kupfer laboratory has established that FA proteins such as FANCA and FANCG phosphorylated, that the FA core complex (composed of at least 5 FA proteins) localizes to at least 3 subcellular compartments, including chromatin, and that the core complex binds to additional non-characterized proteins. This proposal centers on the analysis of posttranslational modifications of the FA proteins FANCA and FANCG and on detecting new binding proteins and determining their function. This would shed light on the long-term goal of the Kupfer laboratory: define the mechanisms of genomic instability caused by FA as well as understand the normal function of the FA proteins. In this proposal the experiments proposed address the central hypothesis: that the phosphorylation of FANCA and FANCG regulate proper localization to chromatin and that a novel FA binding protein, RBM10, has RNA binding activity critical for this localization. The work proposed will 1) determine the cause and effect of FANCA and FANCG phosphorylation, 2) analyze RBM10 and RNA function in the FA core complex, and 3) focus on purifying additional FA core complex and FANCD2 binding proteins, especially from chromatin. This research is significant because it sheds light on a mechanism of genomic instability at the level of the functional genetic unit of the cell: chromatin. Because the response to DNA damage involves numerous intersecting pathways, defining the function of FA proteins will allow us to link these disparate pathways in a mechanism explaining cancer formation.

描述（由申请人提供）：对癌症易感性罕见的遗传疾病的研究，例如Fanconi贫血（FA），已导致整个癌症生物学的开创性进步。 FA的标志是基因组不稳定性和DNA损伤超敏反应，但是FA途径的正常功能或导致患者癌症的机制的正常功能仍然未知。 FA由多个互补组考虑到至少8个克隆基因，其编码蛋白包含很少的功能基序。众所周知，FA途径与其他更明确的途径相互作用，涉及对DNA损伤的细胞反应，例如ATM和BRCA1。 kupfer实验室已经确定，诸如FANCA和FANCG磷酸化的FA蛋白磷酸化，FA核心复合物（由至少5种FA蛋白组成）定位于至少3个亚细胞隔室，包括染色质，核心复合物与其他非 - 非 - 非核心结合到其他非 - 非 - 特征蛋白质。该建议集中在分析FA蛋白Fanca和Fancg的翻译后修饰，以及检测新的结合蛋白并确定其功能上。这将阐明kupfer实验室的长期目标：定义由FA引起的基因组不稳定性的机制，并了解FA蛋白的正常功能。在该提案中，实验提出的解决了中心假设：范卡和粉丝的磷酸化调节适当的定位对染色质，并且一种新型的FA结合蛋白RBM10具有RNA结合活性，对这种定位至关重要。提出的工作将为1）确定FANCA和FANCG磷酸化的原因和影响，2）分析FA核心复合物中的RBM10和RNA功能，以及3）专注于净化额外的FA核心复合物和FANCD2结合蛋白，尤其是来自染色质。这项研究很重要，因为它阐明了细胞功能遗传单位水平的基因组不稳定性机制：染色质。由于对DNA损伤的反应涉及许多相交的途径，因此定义FA蛋白的功能将使我们能够将这些不同的途径连接到解释癌症形成的机制中。