Mechanistic Dissection of the Falconi Anemia Pathway of DNA Damage Response and Repair

法尔科尼贫血 DNA 损伤反应和修复途径的机制剖析

• 批准号: 9899099
• 负责人: Gary M. Kupfer
• 金额: $ 37.18万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899099
• 关键词: Address; Advanced Malignant Neoplasm; Aldehydes; Anemia; Area; BRCA1 Protein; BRCA1 gene; BRCA2 gene; Biochemical; Biological; Biology; Breast; Cancer Biology; Cells; Chemicals; Chromosome Arm; Chromosome Fragility; Chromosomes; Communities; Complex; DNA; DNA Crosslinking; DNA Crosslinking Agent; DNA Damage; DNA Repair; DNA Repair Pathway; DNA biosynthesis; DNA lesion; Defect; Deubiquitination; Development; Diagnosis; Disease; Dissection; Ensure; Etiology; Event; Exhibits; Fanconi Anemia pathway; Fanconi anemia protein; Fanconi' s Anemia; Funding; Genes; Genetic; Genetic Transcription; Genome; Genomic Instability; Genomics; Grant; Hereditary Breast Carcinoma; Human; Hypersensitivity; ID2 gene; Incidence; Joint Ventures; Licensing; Light; Link; Maintenance; Malignant Neoplasms; Mediating; Modeling; Monoubiquitination; Motor; Mutation; Nucleic Acid Binding; Nucleic Acids; Pancreas; Pancytopenia; Pathogenicity; Pathway interactions; Patients; Phenotype; Play; Predisposition; Prevention; Process; Proteins; RNA; Rad51 recombinase; Radiation; Regulation; Research Personnel; Resolution; Resources; Role; Signal Transduction; Structure; Structure-Activity Relationship; System; Testing; Tumor Suppression; Ubiquitination; Work; cancer prevention; cancer therapy; causal variant; cohort; genotoxicity; helicase; homologous recombination; improved; in vivo; inhibitor/antagonist; insight; multidisciplinary; novel; protein complex; repaired; replication stress; research study; response; stem; success; tumorigenesis

Project Summary Proteins from the Fanconi anemia (FA) pathway play an integral role in DNA repair by homologous recombination (HR). 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 and reactive aldehydes 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 breast 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 the novel hypotheses that the FA pathway coordinates the prevention and resolution of genotoxic structures resulting from aberrant transcription events and HR. Aim 1 will focus on the mechanism whereby the ID2 complex and UAF1-containing complexes engage nucleic acid containing structures and activate HR. Aim 2 will explore how the FANCM-BLM axis resolves pathogenic RNA containing and other nucleic acid intermediates in a way that regulates HR activities. 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. In addition, the PIs have enlisted two investigators, Dr. Claudia Wiese and Dr. Andres Aguilera, whose expertise will even more elegantly allow the team to interrogate this novel area of genomic instability. 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.

项目概要 来自范可尼贫血 (FA) 途径的蛋白质在同源 DNA 修复中发挥着不可或缺的作用 重组（HR）。 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房联系起来， 胰腺癌和其他癌症，并且还提供了充分的证据表明 FA 沉默 散发性癌症病因学中的基因。 FA 细胞对辐射和其他 DNA 高度敏感 损伤剂、DNA 交联化学物质和活性醛，特别是容易对 DNA 产生影响的物质 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以及 FA 蛋白功能和物理相互作用的缺陷 表明与家族性乳腺癌蛋白 BRCA1 和 BRCA2 存在重要联系。这 FA/BRCA 依赖性 DNA 损伤反应在癌症抑制中的参与强调 需要了解这种基因组维护途径的机制基础。 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新型 假设 FA 途径协调基因毒性结构的预防和解决 由异常转录事件和 HR 引起的。目标 1 将重点关注机制 ID2 复合物和包含 UAF1 的复合物接合包含核酸的结构并激活 人力资源。目标 2 将探索 FANCM-BLM 轴如何解决含有和其他物质的致病性 RNA 核酸中间体以调节 HR 活动的方式。这个项目的成功在于 由帕特里克·宋博士领导的两个参与耶鲁小组的互补专业知识保证了这一点 和加里·库普弗博士，以及更广泛的耶鲁大学内部异常强大的合作框架 社区。此外，PI 还招募了两名调查员，Claudia Wiese 博士和 Andres 博士 阿奎莱拉（Aguilera）的专业知识将使团队能够更优雅地探究这个新领域 基因组不稳定。这些属性有助于确保具有最大可能影响的调查结果 获得。由于 FA 生物学与一般癌症生物学有交叉，我们的项目承诺 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新的靶点 用于癌症治疗中的操作。