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Function and Regulation of the Fanconi Anemia pathway in DNA repair

范可尼贫血途径在 DNA 修复中的功能和调节

基本信息

批准号：
8957209
负责人：
Younghoon Kee
金额：
$ 43.96万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8957209
关键词：
Accounting BRCA2 gene Binding Binding Sites Biochemical Biological Assay Bone Marrow Cell Maintenance Cells Chromatin Complex DNA DNA Damage DNA Interstrand Crosslinking DNA Repair DNA Repair Pathway Data Deubiquitinating Enzyme Deubiquitination Development Disease Drug resistance Event Failure Fanconi anemia protein Fanconi&apos s Anemia Genes Genetic Genome Stability Genomic Instability Genotoxic Stress Hematopoietic stem cells Hereditary Disease Human Hypersensitivity In Vitro Intervention Investigation Laboratories Lead Ligase Maintenance Malignant Neoplasms Mediating Modeling Modification Molecular Monoubiquitination Multienzyme Complexes Mutate N-terminal Nuclear Pancytopenia Pathogenesis Pathway interactions Patients Physiological Proteins Proteomics Reaction Reactive Oxygen Species Recruitment Activity Regulation Resistance development Role Students Syndrome System Therapeutic Training Ubiquitin Ubiquitination Work base congenital anomaly design dimer homologous recombination insight multicatalytic endopeptidase complex mutant novel public health relevance recombinational repair reconstitution response treatment strategy ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Studying the rare genetic disorder Fanconi Anemia (FA) will provide insight into a normal cellular response mechanism in response to genotoxic stress. FA, a genome instability syndrome, is characterized by congenital anomalies, bone marrow and hematopoietic stem cell maintenance failure, and heightened cellular sensitivity to DNA damaging insults. The fifteen FA proteins that have so far been identified collaborate in the cellular FA pathway to modulate DNA repair mechanisms that resolve DNA interstrand crosslinks. Conversely, heightened activity of the FA pathway and a downstream DNA homologous recombination (HR) repair may be important determinants for developing resistance to DNA damaging agents in some cancers. Thus, understanding the molecular function and regulation of the FA pathway may lead to development of novel targeting strategies for resolving FA disease, as well as for intervention against certain cancers. The central regulatory step in the FA pathway is monoubiquitination of two key FA proteins FANCD2- FANCI, by the multi-subunit nuclear E3 ubiquitin ligase, which consists of at least eight FA proteins. Deficiency in the monoubiquitination of FANCD2 and FANCI accounts for more than 90% of the FA cases, suggesting a critical role of this modification in pathogenesis. USP1 deubiquitinating enzyme and its binding partner UAF1 are also critical for the overall FA-HR repair, in part by deubiquitinating FANCD2-FANCI. In this study, we propose two lines of investigation into the regulation of the FA-HR pathway. In Aim 1, we will identify the substrate recruitment module of the FA E3 ligase complex. We will determine the mechanism how the FANCD2-FANCI heterodimer is recruited to the FA E3 ligase complex prior to their monoubiquitination. In Aim 2, we will determine the role of the USP1-UAF1 deubiquitinating enzyme complex in promoting the FA-HR repair. We will particularly focus on the role of the deubiquitinating enzyme complex in modulating a HR promoting factor RAD51AP1. Successful completion of this work will provide new mechanistic insights into regulation of the FA pathway and into broader aspects of the ubiquitin system in general.

描述（由申请人提供）：研究罕见的遗传性疾病范可尼贫血（FA）将深入了解响应基因毒性应激的正常细胞反应机制。 FA 是一种基因组不稳定综合征，其特征是先天性异常、骨髓和造血干细胞维持失败以及细胞对 DNA 损伤性损伤的敏感性增强。迄今为止已鉴定的 15 种 FA 蛋白在细胞 FA 通路中协同调节 DNA 修复机制，从而解决 DNA 链间交联问题。相反，FA 途径的活性增强和下游 DNA 同源重组 (HR) 修复可能是某些癌症中对 DNA 损伤剂产生耐药性的重要决定因素。因此，了解 FA 途径的分子功能和调节可能会导致开发新的靶向策略来解决 FA 疾病以及针对某些癌症的干预。 FA 途径的中心调节步骤是通过多亚基核 E3 泛素连接酶对两个关键 FA 蛋白 FANCD2-FANCI 进行单泛素化，该连接酶由至少八个 FA 蛋白组成。 FANCD2 和 FANCI 单泛素化缺陷占 FA 病例的 90% 以上，表明这种修饰在发病机制中发挥着关键作用。 USP1 去泛素化酶及其结合伙伴 UAF1 对于整体 FA-HR 修复也至关重要，部分是通过去泛素化 FANCD2-FANCI 实现的。在本研究中，我们提出了 FA-HR 通路调节的两条研究路线。在目标 1 中，我们将鉴定 FA E3 连接酶复合物的底物招募模块。我们将确定 FANCD2-FANCI 异二聚体在单泛素化之前如何招募至 FA E3 连接酶复合物的机制。在目标 2 中，我们将确定 USP1-UAF1 去泛素化酶复合物在促进 FA-HR 修复中的作用。我们将特别关注去泛素化酶复合物在调节 HR 促进因子 RAD51AP1 中的作用。这项工作的成功完成将为 FA 途径的调控和泛素系统的更广泛方面提供新的机制见解。