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: 10320390
• 负责人: Niall George Howlett
• 金额: $ 30.57万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320390
• 关键词: ATAC-seq; Applications Grants; Binding; Biochemistry; Biological Assay; Bone marrow failure; 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; 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.

项目摘要/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、血液系统疾病和 骨髓衰竭、癌症风险增加和过早死亡。 FA 的治疗选择非常多 FA 患者的总体预期寿命有限，仅为 29 岁。 FA 的分子病因学尚不明确 目前尚无基于该疾病生物化学的合理治疗方法 发达。因此，FA 患者及其家人和亲人的预后很差。进步 只有更好地了解这种疾病的分子基础才能实现这一领域的目标， 强调我们提出的研究的重要性。 FA 是由 22 个基因中任何一个的突变引起的。 FA 蛋白的功能是修复 DNA 损伤并 维持染色体稳定性。 FA途径激活的关键步骤是单泛素化 FANCD2 和 FANCI 蛋白，在接触 DNA 损伤剂时出现。单泛素化 FANCD2 和 FANCI 的结合促进它们组装成离散的染色质相关灶。其机制由 然而，FANCD2 和 FANCI 在染色质中的靶向、保留和功能在很大程度上是 未知。重要的是，FANCD2 和 FANCI 单泛素化在 90% 以上的 FA 患者中存在缺陷，并且 FA 患者 BMF 和血液疾病的组成部分。 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 本提案要测试的假设：我们假设 FANCD2 蛋白是二价核小体 阅读器，通过新发现的甲基结合域结合甲基化组蛋白并结合 通过其 CUE 泛素结合域泛素化组蛋白。核小体结合促进局部染色质 在 DNA 损伤位点进行重塑，以促进下游 DNA 修复蛋白的招募。 因此，FANCD2 的丢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 3 年 SHINE II 的总体目标 R01 研究计划旨在阐明 FA 和 FA 之间联系的分子基础 染色质可塑性。我们期望阐明 FA 途径和 染色质可塑性有潜力开辟基于表观遗传学的治疗探索新途径 和 FA 的机会。