Mechanistic Dissection of the Fanconi Anemia Pathway of DNA Damage Response and R

DNA 损伤反应和 R 范可尼贫血途径的机制剖析

• 批准号: 8505689
• 负责人: Gary M. Kupfer
• 金额: $ 34.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505689
• 关键词: Address; BRCA1 Protein; BRCA2 gene; Biochemical; Biological; Biology; Breast; Cancer Biology; Cells; Chemicals; Chromosome Fragility; Chromosomes; Communities; Complex; DNA; DNA Binding; DNA Crosslinking Agent; DNA Damage; DNA Repair; DNA Repair Pathway; DNA lesion; DNA repair protein; DNA-Protein Interaction; Defect; Deubiquitination; Diagnosis; Disease; Dissection; Ensure; Etiology; Exhibits; Fanconi anemia protein; Fanconi' s Anemia; Genes; Genetic; Genome; Genomics; Grant; Hereditary Breast Carcinoma; Human; Incidence; Joint Ventures; Light; Link; Maintenance; Malignant Neoplasms; Mediating; Modeling; Monoubiquitination; Mutation; Oncogenes; Pancreas; Pancytopenia; Pathway interactions; Post-Translational Protein Processing; Predisposition; Process; Proteins; Radiation; Resources; Role; Signal Transduction; Staging; Stress; Structure-Activity Relationship; Synapses; System; Testing; Tumor Suppression; Ubiquitination; Work; base; cancer prevention; cancer therapy; cohort; improved; in vivo; inhibitor/antagonist; insight; multidisciplinary; novel; public health relevance; recombinase; repaired; research study; response; stem; success; tumorigenesis

DESCRIPTION (provided by applicant): Fanconi anemia (FA) is a multigenic disorder marked by progressive bone marrow failure and a strong cancer predisposition. Numerous studies have linked mutations in FA genes to familial breast, pancreatic, and other cancers, and have also provided ample evidence to implicate silencing of FA genes in the etiology of sporadic cancers. FA cells are hypersensitive to radiation and other DNA damaging agents, DNA crosslinking chemicals in particular, prone to DNA replicative stress, and exhibit chromosome fragility. These phenotypic manifestations stem from defects in DNA damage signaling and repair, and FA protein functional and physical interactions have indicated an important link to the familial breas cancer proteins BRCA1 and BRCA2. The involvement of the FA/BRCA-dependent DNA damage response in cancer suppression underscores the need to understand the mechanistic underpinnings of this genome maintenance pathway. In this project, we will employ a combination of biochemical and in vivo approaches to test hypotheses regarding the manner by which protein-protein and protein-DNA interactions involving key FA and partner proteins mediate the post-translational modifications of the FANCI-FANCD2 complex and also the homology-directed repair of damaged DNA. The success of this project is assured by the complementary expertise of the two participating Yale groups, led by Dr. Patrick Sung and Dr. Gary Kupfer, and an exceptionally strong collaborative framework within the broader Yale community. These attributes help ensure that findings of the highest possible impact will be obtained. Since the biology of FA intersects with cancer biology in general, our project promises to shed light on critical processes of genomic surveillance as well as common themes of oncogenesis. We expect our studies to yield insight into common pathways of cancer and to identify novel targets for manipulation in cancer therapy.

描述（由申请人提供）：Fanconi贫血（FA）是一种以进行性骨髓衰竭和强烈的癌症易感性为特征的多基因疾病。大量研究将FA基因的突变与家族性乳腺癌，胰腺和其他癌症联系起来，并且还提供了充足的证据，使FA基因的沉默暗示了散发性癌症的病因。 FA细胞对辐射和其他DNA损伤剂高度敏感，尤其是DNA交联化学物质，容易发生DNA复制应激，并表现出染色体脆弱性。这些表型表现源于DNA损伤信号传导和修复中的缺陷，FA蛋白功能和物理相互作用表明与家族性breas癌蛋白BRCA1和BRCA2的重要联系。 FA/BRCA依赖性DNA损伤反应在癌症抑制中的参与强调了了解该基因组维持途径的机械基础的必要性。在该项目中，我们将采用生化和体内方法的组合来测试有关蛋白质蛋白质蛋白和蛋白质-DNA相互作用涉及关键FA和伴侣蛋白的蛋白质 - 蛋白质 - DNA相互作用的方式，并介导了Fanci-Fancd2复合物的翻译后修饰，也是损坏的DNA的同源指导修复。由帕特里克·昂格（Patrick Sung）博士和加里·库普弗（Gary Kupfer）博士领导的两个参与的耶鲁团体的补充专业知识确保了这个项目的成功，以及在更广泛的耶鲁大学社区中的一个异常强大的合作框架。 这些属性有助于确保将获得最高影响的发现。由于FA的生物学一般与癌症生物学相交，因此我们的项目有望阐明基因组监测的关键过程以及肿瘤发生的常见主题。我们希望我们的研究能够深入了解癌症的常见途径，并确定癌症治疗中操纵的新目标。