Genetic Framework and Molecular Mechanism of Fanconi Anemia

范可尼贫血的遗传框架和分子机制

• 批准号: 8994281
• 负责人: LEI LI
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-12 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8994281
• 关键词: Address; Aplastic Anemia; Biological Models; Biology; Bypass; Cell Survival; Cells; Chromosome Breakage; Chromosome abnormality; Cisplatin; Clinical; Complex; Congenital Abnormality; DNA; DNA Crosslinking Agent; DNA Damage; DNA Interstrand Crosslinking; DNA Repair; DNA lesion; DNA replication fork; DNA-protein crosslink; Defect; Disease; Drosophila genus; Enzymes; Exhibits; Fanconi Anemia Complementation Group L Protein; Fanconi Anemia pathway; Fanconi anemia protein; Fanconi' s Anemia; Frequencies; Genes; Genetic; Genetic Models; Genotoxic Stress; Hereditary Disease; Hypersensitivity; Investigation; Ionizing radiation; Knock-out; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Melphalan; Modality; Modeling; Molecular; Molecular Structure; Monoubiquitination; Mutation; Nuclear; Outcome; Pancytopenia; Pathway interactions; Patients; Pharmaceutical Preparations; Polymerase; Predisposition; Process; Proteins; Reaction; Reagent; Recruitment Activity; Reporter; Series; Site; System; Tertiary Protein Structure; Testing; Therapeutic Intervention; Transcriptional Activation; Treatment outcome; Tumor Suppressor Genes; Variant; Vertebrates; Work; Yeasts; base; cancer therapy; chemotherapy; crosslink; design; gene product; genome integrity; improved; in vivo; loss of function; mutant; new therapeutic target; novel; protein function; repaired; research study; response; targeted treatment; ubiquitin-protein ligase

Project Summary Fanconi anemia (FA) is a recessive disorder caused by deficient DNA damage repair. FA patients exhibit aplastic anemia, congenital abnormalities, and profoundly elevated cancer occurrence. Cells derived from FA patients are hypersensitivity to DNA crosslinking agents and highly susceptible to chromosome breakage under genotoxic stress. To date, 15 autosomal and 1 X-linked genes are designated as causative genes for FA, but the molecular structure of the FA pathway remains largely unclear. Lack of defined genetic model systems and a scarcity of recognizable protein domains in most FA proteins are among the major obstacles impeding the advance of FA biology. The main objective of this proposal is to establish the genetic framework of the FA pathway and to elucidate molecular functions of key FA proteins. We begin to approach these problems by systematically constructing somatic cellular knockout models. Our preliminary investigations insinuate a hypothesis that different FA proteins form distinct functional modules to accomplish the DNA damage-induced FA pathway activation, which enables the recruitment of DNA damage-processing enzymes. We plan to test this hypothesis with three specific aims: (1) Define the epistatic relationships among classic FA gene products, which will mitigate a visible void in genetic connections among Fanconi anemia genes. (2) Dissect the functional integration of the FA core E3 ligase complex which contains several FA proteins with unknown functions. (3) Determine whether DNA-protein crosslinks are prevalent endogenous lesions processed by the FA pathway. Elucidation of the FA pathway should have a significant impact in advancing the understanding of fundamental cellular mechanisms protecting genome integrity. More importantly, FA pathway components are potential target for therapeutic intervention. The FA pathway functions primarily in resolving replication fork- blocking DNA lesions. This type of lesions is exemplified by DNA crosslinks most frequently generated by bifunctional alkylating chemotherapeutic modalities, such cisplatin and melphalan, and by DNA-protein crosslinks produced with high frequency from ionizing radiation exposure. For example, clinical response of many ovarian cancers to cisplatin treatment is dictated by their FA pathway status. In summary, this project is aimed at delineating the molecular pathological mechanism of Fanconi anemia with the immediate benefit of uncovering novel therapeutic targets to the improve cancer treatment outcomes.

项目摘要 Fanconi贫血（FA）是由DNA损伤修复不足引起的隐性疾病。 fa 患者表现出性质贫血，先天性异常和癌症升高 发生。源自FA患者的细胞是对DNA交联药的超敏反应， 在遗传毒性应激下高度容易受到染色体破裂的影响。迄今为止，15个常染色体和 1个X连锁基因被指定为FA的致病基因，但分子结构的分子结构 FA途径在很大程度上不清楚。缺乏确定的遗传模型系统和稀缺性 大多数FA蛋白中可识别的蛋白质结构域是阻碍 FA生物学的发展。该提案的主要目的是建立遗传框架 FA途径并阐明关键FA蛋白的分子功能。我们开始 通过系统地构建体细胞敲除模型来解决这些问题。我们的 初步研究暗示了不同的FA蛋白形成不同的假设 实现DNA损伤诱导的FA途径激活的功能模块，该模块激活 实现DNA损伤处理酶的募集。我们计划检验这个假设 有三个特定的目的：（1）定义经典FA基因产品之间的上皮关系， 这将减轻范科尼贫血基因之间的遗传连接中的可见空隙。 （2） 剖析FA核E3连接酶复合物的功能整合，其中包含几个FA 具有未知功能的蛋白质。 （3）确定DNA-蛋白交联是否普遍 FA途径处理的内源性病变。 FA途径的阐明应具有 在促进对基本细胞机制的理解方面的重要影响 保护基因组完整性。更重要的是，FA途径组件是潜在的目标 治疗干预。 FA途径主要用于解决复制叉 - 阻塞DNA病变。这种类型的病变最常用DNA交叉链接来体现 由双功能烷基化的化学治疗方式（例如顺铂和梅尔法兰）产生 以及通过电离辐射暴露的高频产生的DNA-蛋白交联。 例如，许多卵巢癌对顺铂治疗的临床反应取决于其 FA路径状态。总而言之，该项目旨在描述分子病理 法科尼贫血的机制，具有揭开新型治疗的直接益处 改善癌症治疗结果的目标。