Role of Deubiquitination in Fanconi Anemia Cancer Susceptibility Pathway

去泛素化在范可尼贫血癌症易感性途径中的作用

• 批准号: 7922972
• 负责人: Tony Tung Huang
• 金额: $ 21.23万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922972
• 关键词: Binding; Cancer Susceptibility Pathway; Cells; Chromatin; Complex; DNA Damage; DNA Interstrand Cross-Link Repair; DNA Repair; Defect; Deubiquitinating Enzyme; Deubiquitination; Enzymes; Equilibrium; Event; Fanconi anemia protein; Fanconi' s Anemia; Gene Family; General Population; Genes; Genome; Genome Stability; Genomic Instability; Human; Inherited; Laboratories; Lead; Libraries; Maintenance; Malignant Neoplasms; Molecular; Monoubiquitination; Mutate; Mutation; Pathway interactions; Patients; Play; Predisposition; Process; Proteins; RNA Interference; Regulation; Research; Role; Screening procedure; Signal Transduction; Syndrome; System; Tumor Suppression; Ubiquitin; Ubiquitination; base; cancer initiation; early onset; in vivo; member; mutant; novel; public health relevance; response; tumorigenesis

DESCRIPTION (provided by applicant): Inherited or acquired deficiencies in genome stability pathways are known to cause a variety of human pathological conditions, including early onset cancer. The familial genome instability or cancer susceptibility syndrome, Fanconi Anemia (FA), is caused by mutations in 1 of at least 13 FA genes. Biallelic mutations in some of these genes also occur in cancers of non-FA patients, implicating these genes in tumor suppression or genome maintenance among the general population. These genes act in a common molecular pathway that modulates DNA repair, especially the repair of DNA interstrand cross-links. Protein ubiquitination and deubiquitination are dynamic processes implicated in the regulation of numerous cellular pathways. Monoubiquitination of the FA protein FANCD2 appears to be critical in the repair of DNA damage because many of the proteins that are mutated in FA are required for FANCD2 ubiquitination. By screening a gene family RNAi library, we identified a deubiquitinating enzyme as a novel component of the FA pathway. Despite the number of recent studies that have helped identify key players for the activation of the FA pathway, it is still unclear how the regulation of the FA pathway is achieved. The research conducted in my laboratory is directed towards understanding the delicate balance between the positive and negative regulators of ubiquitination in the FA pathway. The proposed research concerns enzymes of the ubiquitin system controlling DNA repair and genome stability. Accumulating evidence indicates that defects in the DNA damage response can lead to cancer initiation. The results of our studies will help to define the molecular mechanisms of the Fanconi Anemia pathway and how dysregulation of this pathway can lead to oncogenesis. PUBLIC HEALTH RELEVANCE The familial genome instability or cancer susceptibility syndrome, Fanconi Anemia (FA), is caused by mutations in 1 of at least 13 FA genes. Biallelic mutations in some of these genes also occur in cancers of non-FA patients, implicating these genes in tumor suppression or genome maintenance among the general population. The results of our studies will help to define the molecular mechanisms of the Fanconi Anemia pathway and how dysregulation of this pathway can lead to oncogenesis.

描述（由申请人提供）：已知基因组稳定性途径的遗传性或后天性缺陷会导致多种人类病理状况，包括早发性癌症。家族性基因组不稳定或癌症易感性综合征范可尼贫血 (FA) 是由至少 13 个 FA 基因中的 1 个基因突变引起的。其中一些基因的双等位基因突变也发生在非 FA 患者的癌症中，这表明这些基因与普通人群的肿瘤抑制或基因组维持有关。这些基因在调节 DNA 修复，特别是 DNA 链间交联的修复的共同分子途径中发挥作用。蛋白质泛素化和去泛素化是涉及多种细胞途径调节的动态过程。 FA 蛋白 FANCD2 的单泛素化似乎对于 DNA 损伤的修复至关重要，因为 FA 中的许多突变蛋白都是 FANCD2 泛素化所必需的。通过筛选基因家族 RNAi 文库，我们确定了一种去泛素化酶作为 FA 途径的新成分。尽管最近有大量研究帮助确定了 FA 途径激活的关键参与者，但仍不清楚 FA 途径的调节是如何实现的。我实验室进行的研究旨在了解 FA 途径中泛素化的正负调节因子之间的微妙平衡。拟议的研究涉及控制 DNA 修复和基因组稳定性的泛素系统酶。越来越多的证据表明 DNA 损伤反应的缺陷可能导致癌症的发生。我们的研究结果将有助于确定范可尼贫血途径的分子机制以及该途径的失调如何导致肿瘤发生。 公共健康相关性家族基因组不稳定或癌症易感性综合征范可尼贫血 (FA) 是由至少 13 个 FA 基因中的 1 个基因突变引起的。其中一些基因的双等位基因突变也发生在非 FA 患者的癌症中，这表明这些基因与普通人群的肿瘤抑制或基因组维持有关。我们的研究结果将有助于确定范可尼贫血途径的分子机制以及该途径的失调如何导致肿瘤发生。