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：
9012411
负责人：
Niall George Howlett
金额：
$ 6.5万
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 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9012411
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 Health 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

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（由申请人提供）：Fanconi贫血（FA）是一种罕见的遗传疾病，其特征是小儿骨髓衰竭和先天性异常。在获得骨髓衰竭的情况下，FA基因也经常被突变。 FA蛋白与FA-BRCA途径中的肿瘤抑制蛋白BRCA1和BRCA2（FANCD1）合作，以修复受损的DNA并防止细胞转化。 FA-BRCA途径激活的关键步骤是FANCD2和FANCI蛋白的单泛素体。重要的是，FANCD2和FANCI单泛素化的细胞调节仍然知之甚少。此外，DNA损伤响应中单泛素化的FANCD2和FANCI的生理功能在很大程度上仍然未知。该研究建议的主要目标是系统地解决这些关键的未解决问题。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调节DNA损伤诱导的fancd2单素化中起着重要作用。此外，在使用硅生物信息学方法中，我们已经确定了一个假定的泛素结合结构域（UBD）和FANCD2中的泛素类蛋白样域（UBL）。初步实验已经证实了fancd2和泛素之间的非共价相互作用。在此提案中，我们计划系统地表征p21的作用以及推定的UBD和UBL结构域，在FANCD2的单泛素化以及FA-BRCA途径的激活中。由于缺陷的FANCD2和FANCI单泛素化是> 90％的FA患者的细胞特征，以及一般（非FA）种群中骨髓aplasia病例的一部分，因此对这种反跨性后修饰的调节和功能的研究则具有更大的理解，可以更了解骨骨髓维持和静止。