Chromatin State Alterations in Fanconi Anemia Hematologic Disease and Bone Marrow Failure

范可尼贫血血液疾病和骨髓衰竭中的染色质状态改变

• 批准号: 10078631
• 负责人: Niall George Howlett
• 金额: $ 38.44万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078631
• 关键词: ATAC-seq; Applications Grants; Binding; Biochemistry; Biological Assay; Cells; Chromatin; Chromosomal Instability; Chromosomal Stability; Complement; Congenital Abnormality; DNA Damage; DNA Repair; DNA Repair Gene; Data; Disease; Enzymes; Epigenetic Process; Etiology; Exposure to; FANCD2 protein; Family; Fanconi Anemia pathway; Fanconi anemia protein; Fanconi' s Anemia; General Population; Genes; Genetic Diseases; Goals; Hematological Disease; Hematopoietic Stem Cell Transplantation; Histones; Lead; Life Expectancy; Link; Methyltransferase; Molecular; Molecular Chaperones; Monoubiquitination; Mutation; Nucleosomes; Pancytopenia; Pathogenesis; Patients; Premature Mortality; Prognosis; Proteins; Publishing; Reader; Research Project Grants; Research Proposals; Role; Site; Testing; Therapeutic; Therapeutic Intervention; Ubiquitin; base; cancer risk; chromatin remodeling; gamma-Glutamyl Hydrolase; improved; loved ones; novel; p53-binding protein 1; protein function; recruit; ubiquitin ligase

PROJECT SUMMARY/ABSTRACT: Fanconi anemia (FA) is a genetic disease characterized by congenital abnormalities, hematologic disease and bone marrow failure, increased cancer risk, and premature mortality. Therapeutic options for FA are extremely limited and the overall life expectancy of FA patients is only 29 years. The molecular etiology of FA is poorly understood and no rational therapeutic approaches based on the biochemistry of this disease have been developed. Consequently, the prognosis for FA patients - and their families and loved ones - is poor. Progress in this field will only be achieved by a greater understanding of the molecular basis of this disease, underscoring the significance of our proposed studies. FA is caused by mutations in any one of 22 genes. The FA proteins function to repair DNA damage and to maintain chromosome stability. A key step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins, which occurs upon exposure to DNA damaging agents. The monoubiquitination of FANCD2 and FANCI promotes their assembly into discrete chromatin-associated foci. The mechanisms by which FANCD2 and FANCI are targeted to, retained in, and function within chromatin are, however, largely unknown. Importantly, FANCD2 and FANCI monoubiquitination is defective in >90% of FA patients and integral to FA patient BMF and hematologic disease. Our preliminary data, and recently published studies from our group and others, have shaped the novel hypothesis to be tested in this proposal: We hypothesize that the FANCD2 protein is a bivalent nucleosome reader, binding to methylated histones via a newly-discovered methyl-binding domain and binding to ubiquitinated histones via its CUE ubiquitin-binding domain. Nucleosome binding promotes localized chromatin remodeling at sites of DNA damage to facilitate the recruitment of downstream DNA repair proteins. Consequently, loss or mutation of FANCD2 will be manifested as global alterations of chromatin state, defective DNA repair, and chromosome instability. In summary, the overarching goal of our 3-year SHINE II R01 research proposal is to elucidate the molecular underpinnings of the connections between FA and chromatin plasticity. We anticipate that elucidation of the mechanistic links between the FA pathway and chromatin plasticity has the potential to open up a new avenue of epigenetics-based therapeutic exploration and opportunity for FA.

项目总结/摘要： 范可尼贫血（FA）是一种遗传性疾病，其特征是先天性异常、血液病和 骨髓衰竭、癌症风险增加和过早死亡。FA的治疗选择非常 有限，FA患者的总体预期寿命仅为29岁。FA的分子病因学尚不清楚， 目前还没有基于这种疾病的生物化学的合理治疗方法， 开发因此，FA患者及其家人和亲人的预后很差。进展 只有更好地理解这种疾病的分子基础， 强调了我们提出的研究的重要性。 FA是由22个基因中的任何一个突变引起的。FA蛋白的功能是修复DNA损伤， 保持染色体稳定。FA途径活化的关键步骤是将FA的单泛素化。 FANCD 2和FANCI蛋白，其在暴露于DNA损伤剂时发生。单倍喹他啶 FANCD 2和FANCI的表达促进它们组装成离散的染色质相关灶。的机制 然而，FANCD 2和FANCI靶向、保留在染色质中并在染色质中起作用的部位在很大程度上是细胞的。 未知重要的是，FANCD 2和FANCI单泛素化在>90%的FA患者中是有缺陷的， FA患者BMF和血液病不可或缺。 我们的初步数据，以及我们小组和其他人最近发表的研究，塑造了这部小说 在本提案中有待检验的假设：我们假设FANCD 2蛋白是一个二价核小体 阅读器，通过新发现的甲基结合结构域结合甲基化组蛋白，并结合 泛素化组蛋白通过其CUE泛素结合域。核小体结合促进局部染色质 在DNA损伤的位点重塑，以促进下游DNA修复蛋白的募集。 因此，FANCD 2的缺失或突变将表现为染色质状态的整体改变， DNA修复缺陷和染色体不稳定。总之，我们为期3年的SHINE II的总体目标是 R 01的研究计划是阐明FA和 染色质可塑性我们预计，阐明FA途径与 染色质可塑性有可能为基于表观遗传学的治疗探索开辟一条新的途径 给FA的机会。