Regulation of the Mono-Ubiquitination of the Fanconi Anemia D2 Protein

Fanconi 贫血 D2 蛋白单泛素化的调控

• 批准号: 8527272
• 负责人: Niall George Howlett
• 金额: $ 3.09万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527272
• 关键词: 26S proteasome; Acute Myelocytic Leukemia; Address; Age; Aplastic Anemia; Architecture; BRCA1 gene; BRCA2 gene; Binding; Biochemical; Bioinformatics; Biology; Bone Marrow; Cancer-Predisposing Gene; Cause of Death; Cell Lineage; Cell physiology; Cells; Childhood; Chromatin; Computer Simulation; Congenital Abnormality; Coupled; Covalent Interaction; DNA Damage; DNA Repair; DNA repair protein; DNA-Directed DNA Polymerase; Diagnostic; Disease; Dysmyelopoietic Syndromes; Etiology; FANCD2 protein; Fanconi Anemia-BRCA Pathway; Fanconi anemia protein; Fanconi' s Anemia; Functional disorder; Genes; Goals; Hematopoiesis; Hematopoietic; Hereditary Disease; Holoenzymes; Incidence; Inherited; Lead; Maintenance; Maps; Marrow; Mediating; Modeling; Molecular; Mono-S; Mutate; Pancytopenia; Pathway interactions; Patients; Physiological; Play; Polyubiquitin; Population Study; Post-Translational Protein Processing; Proteins; Proteolysis; Rare Diseases; Regulation; Research Proposals; Role; Saccharomyces cerevisiae; Site-Directed Mutagenesis; Somatic Mutation; Testing; Therapeutic; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination; base; cell growth regulation; cytopenia; improved; insight; malignant breast neoplasm; metaplastic cell transformation; mouse model; multicatalytic endopeptidase complex; novel; oncoprotein p21; prevent; protein function; public health relevance; research study; response

DESCRIPTION (provided by applicant): Fanconi anemia (FA) is a rare genetic disease characterized by pediatric bone marrow failure and congenital abnormalities. The FA genes are also frequently mutated in cases of acquired bone marrow failure. The FA proteins function cooperatively with the tumor suppressor proteins BRCA1 and BRCA2 (FANCD1) in the FA- BRCA pathway to repair damaged DNA and to prevent cellular transformation. A critical step in the activation of the FA-BRCA pathway is the mono-ubiquitinaton of the FANCD2 and FANCI proteins. Importantly, the cellular regulation of FANCD2 and FANCI mono-ubiquitination remains poorly understood. Furthermore, the physiological function of mono-ubiquitinated FANCD2 and FANCI in the DNA damage response remains largely unknown. The major goal of this research proposal is to systematically address these critical unanswered questions. Towards this goal, we have recently determined that the p21 cyclin dependent kinase inhibitor plays an important role in the regulation of DNA damage-inducible FANCD2 mono-ubiquitination. Furthermore, using in silico bioinformatic approaches, we have identified a putative ubiquitin-binding domain (UBD) and a proximal ubiquitin-like domain (UbL) in FANCD2. Preliminary experiments have confirmed a non- covalent interaction between FANCD2 and ubiquitin. In this proposal, we plan to systematically characterize the role of p21, as well as the putative UBD and UbL domains, in the mono-ubiquitination of FANCD2 and the activation of the FA-BRCA pathway. As defective FANCD2 and FANCI mono-ubiquitination is a cellular feature of >90% of FA patients as well as a subset of cases of marrow aplasia in the general (non-FA) population, the study of the regulation and function of this post-translational modification stands to impart a greater understanding of bone marrow maintenance and stability in general. PUBLIC HEALTH RELEVANCE: Fanconi anemia (FA) is a rare disease characterized by progressive bone marrow failure. The FA pathway is also frequently inactivated in cases of acquired bone marrow failure. A greater understanding of the regulation and function of the FA proteins will lead to improved diagnostic and therapeutic approaches to FA, and improve our understanding of bone marrow maintenance and stability in general.

描述（由申请人提供）：范可尼贫血（FA）是一种罕见的遗传性疾病，其特征是儿科骨髓衰竭和先天性异常。在获得性骨髓衰竭的情况下，FA基因也经常发生突变。FA蛋白与肿瘤抑制蛋白BRCA 1和BRCA 2（FANCD 1）在FA-BRCA途径中协同作用，以修复受损的DNA并防止细胞转化。FA-BRCA途径活化的关键步骤是FANCD 2和FANCI蛋白的单泛素化。重要的是，FANCD 2和FANCI单泛素化的细胞调节仍然知之甚少。此外，单泛素化FANCD 2和FANCI在DNA损伤反应中的生理功能在很大程度上仍然未知。这项研究计划的主要目标是系统地解决这些关键的未回答的问题。为了实现这一目标，我们最近已经确定，p21细胞周期蛋白依赖性激酶抑制剂在DNA损伤诱导的FANCD 2单泛素化的调节中起着重要作用。此外，使用计算机生物信息学方法，我们已经确定了一个假定的泛素结合结构域（UBD）和近端泛素样结构域（UbL）在FANCD 2。初步实验证实了FANCD 2和泛素之间的非共价相互作用。在这个提议中，我们计划系统地表征p21，以及推定的UBD和UbL结构域在FANCD 2的单泛素化和FA-BRCA通路的激活中的作用。由于缺陷性FANCD 2和FANCI单泛素化是>90%的FA患者以及一般（非FA）人群中骨髓发育不全病例的子集的细胞特征，因此对这种翻译后修饰的调节和功能的研究有助于更好地理解骨髓的维持和稳定性。 公共卫生相关性：范可尼贫血（FA）是一种以进行性骨髓衰竭为特征的罕见疾病。在获得性骨髓衰竭的情况下，FA途径也经常失活。更好地了解FA蛋白的调节和功能将导致FA的诊断和治疗方法的改进，并提高我们对骨髓维持和稳定性的理解。