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: 8641673
• 负责人: Gary M. Kupfer
• 金额: $ 33.51万
• 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/8641673
• 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）：范可尼贫血（FA）是一种多基因疾病，其特征是进行性骨髓衰竭和强烈的癌症倾向。许多研究已将 FA 基因突变与家族性乳腺癌、胰腺癌和其他癌症联系起来，并提供了充足的证据表明 FA 基因沉默与散发性癌症的病因有关。 FA 细胞对辐射和其他 DNA 损伤剂（尤其是 DNA 交联化学物质）高度敏感，容易受到 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的缺陷，并且 FA 蛋白的功能和物理相互作用表明与家族性乳腺癌蛋白 BRCA1 和 BRCA2 存在重要联系。 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制基础的必要性。在这个项目中，我们将采用生化和体内方法相结合的方法来测试有关涉及关键 FA 和伙伴蛋白的蛋白质-蛋白质和蛋白质-DNA 相互作用介导 FANCI-FANCD2 复合物翻译后修饰的方式的假设，以及以及受损 DNA 的同源定向修复。由 Patrick Sung 博士和 Gary Kupfer 博士领导的两个参与的耶鲁小组的互补专业知识以及更广泛的耶鲁社区内异常强大的合作框架确保了该项目的成功。 这些属性有助于确保获得尽可能具有最大影响力的调查结果。由于 FA 生物学与癌症生物学总体上有交叉，我们的项目有望揭示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靶点。