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

Fanconi 贫血 D2 蛋白单泛素化的调控

基本信息

批准号：
8435367
负责人：
Niall George Howlett
金额：
$ 34.27万
依托单位：
UNIVERSITY OF RHODE ISLAND
依托单位国家：
美国
项目类别：
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/8435367
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&apos 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

项目摘要

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.

描述（申请人提供）：范可尼贫血（FA）是一种罕见的遗传性疾病，其特征是小儿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 FA-BRCA 通路中的肿瘤抑制蛋白 BRCA1 和 BRCA2 (FANCD1) 协同发挥作用，修复受损的 DNA 并防止细胞转化。 FA-BRCA 途径激活的关键步骤是 FANCD2 和 FANCI 蛋白的单泛素化。重要的是，FANCD2 和 FANCI 单泛素化的细胞调节仍然知之甚少。此外，单泛素化 FANCD2 和 FANCI 在 DNA 损伤反应中的生理功能仍然很大程度上未知。本研究计划的主要目标是系统地解决这些尚未解答的关键问题。为了实现这一目标，我们最近确定p21细胞周期蛋白依赖性激酶抑制剂在DNA损伤诱导的FANCD2单泛素化的调节中发挥重要作用。此外，利用计算机生物信息学方法，我们在 FANCD2 中鉴定了一个推定的泛素结合域 (UBD) 和一个近端泛素样域 (UbL)。初步实验已证实FANCD2与泛素之间存在非共价相互作用。在本提案中，我们计划系统地表征 p21 以及假定的 UBD 和 UbL 结构域在 FANCD2 单泛素化和 FA-BRCA 途径激活中的作用。由于 FANCD2 和 FANCI 单泛素化缺陷是 90% 以上的 FA 患者以及一般（非 FA）人群中骨髓再生障碍病例的一个子集的细胞特征，因此对这种后处理的调节和功能的研究翻译修饰有助于更好地理解骨髓的维持和稳定性。