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: 8040615
• 负责人: Niall George Howlett
• 金额: $ 26.06万
• 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/8040615
• 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; 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(申请人提供)：Fanconi贫血(FA)是一种罕见的遗传性疾病，以儿童骨髓衰竭和先天性异常为特征。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FA-BRCA途径中的肿瘤抑制蛋白BRCA1和BRCA2(FANCD1)协同作用，修复受损的DNA，防止细胞转化。FA-BRCA途径激活的关键步骤是FANCD2和FANCI蛋白的单一泛素化。重要的是，FANCD2和FANCI单一泛素化的细胞调控仍然知之甚少。此外，单一泛素化的FANCD2和FANCI在DNA损伤反应中的生理功能在很大程度上仍不清楚。这项研究提案的主要目标是系统地解决这些关键的悬而未决的问题。为此，我们最近确定了p21细胞周期蛋白依赖性激酶抑制因子在DNA损伤诱导的FANCD2单泛素化调节中起重要作用。此外，利用电子生物信息学方法，我们在FANCD2中发现了一个假定的泛素结合结构域(UBD)和一个近端的泛素样结构域(UBL)。初步实验证实FANCD2和泛素之间存在非共价相互作用。在这个建议中，我们计划系统地表征p21以及可能的UBD和UBL结构域在FANCD2的单一泛素化和FA-BRCA途径激活中的作用。由于FANCD2和FANCI单一泛素化缺陷是90%的FA患者的细胞特征以及普通(非FA)人群中骨髓再生障碍性疾病的一个子集，对这种翻译后修饰的调节和功能的研究将使我们更好地理解骨髓的维护和稳定性。 公共卫生相关性：Fanconi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。更多地了解FA蛋白的调节和功能将有助于改进FA的诊断和治疗方法，并从总体上提高我们对骨髓维持和稳定性的理解。