The role of microhomology-mediated end joining in Fanconi anemia pathogenesis

微同源介导的末端连接在范可尼贫血发病机制中的作用

基本信息

  • 批准号:
    10580006
  • 负责人:
  • 金额:
    $ 46.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-01 至 2024-01-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Children with Fanconi anemia (FA) demonstrate developmental disorders that include short stature, musculoskeletal defects, cancer predisposition, bone marrow failure (BMF) and anemia. In a significant proportion of cases, FA is associated with biallelic mutations in the hereditary breast and ovarian cancer (HBOC) genes. Pre-clinical FA studies have largely relied on transgenic animal models. However, currently available FA mouse models are born without developmental defects and hematological abnormalities have to be chemically induced. Our laboratory has developed a new Brca1CC mutant mouse model with a 3-amino acid deletion in the coiled-coil (CC) domain of Brca1 that specifically disrupts the Brca1-Palb2 association, resulting in loss of Rad51 loading and HR deficiency. Notably, Brca1CC homozygous mice are born at sub-Mendelian ratios, and neo-natal mice demonstrate a range of phenotypes analogous to FA in humans, including short stature, BMF with severe anemia, and adult mice develop leukemia. Therefore, Brca1CC mice closely resemble human FA and provide a new tool to gain unprecedented insight into biological pathways that underpin FA etiology. Both homologous recombination (HR) and microhomology-mediated end joining (MMEJ) are double stranded DNA break (DSB) repair pathways that are initiated by DNA end resection, a process where DSBs are resected by nucleases to form single stranded (ss)DNA regions. In preliminary data, we examined human FA patient cells, as well as Brca1CC MEFs, for HR and MMEJ activity. Interestingly, while HR was lowered, MMEJ was hyperactivated in FA cell lines. We now hypothesize that hyperactive DNA end resection and MMEJ promote the molecular pathogenesis of FA. We will address the following Specific Aims: 1) identify DNA repair pathways that are hyperactive in FA; 2) uncover mechanisms that promote FA embryonic development and pathogenesis; and 3) examine the effects of MMEJ inhibition on FA pathogenesis. Collectively, the proposed experiments will yield new insight into DNA repair mechanisms that promote genome instability and FA.
项目摘要 患有范可尼贫血(FA)的儿童表现出发育障碍,包括身材矮小, 肌肉骨骼缺陷、癌症易感性、骨髓衰竭(BMF)和贫血。显著 在遗传性乳腺癌和卵巢癌(HBOC)中,FA与双等位基因突变相关 基因.临床前FA研究主要依赖于转基因动物模型。目前,FA 小鼠模型出生时没有发育缺陷, 诱导。我们的实验室已经开发了一种新的Brca 1CC突变小鼠模型,该模型在Brca 1CC基因中缺失了3个氨基酸。 Brca 1的卷曲螺旋(CC)结构域,特异性破坏Brca 1-Palb 2结合,导致Rad 51丢失 负荷和HR不足。值得注意的是,Brca 1CC纯合子小鼠以亚孟德尔比率出生, 小鼠表现出一系列与人类FA相似的表型,包括身材矮小、BMF伴严重 贫血,成年小鼠发展成白血病。因此,Brca 1CC小鼠与人FA非常相似, 新的工具,以获得前所未有的深入了解生物学途径的基础FA病因。同源的 重组(HR)和微同源介导的末端连接(MMEJ)是双链DNA断裂(DSB) 由DNA末端切除启动的修复途径,这是一个通过核酸酶切除DSB的过程, 形成单链(ss)DNA区域。在初步数据中,我们检查了人类FA患者细胞,以及 Brca 1CC MEF,用于HR和MMEJ活性。有趣的是,当HR降低时,FA中的MMEJ过度激活, 细胞系我们现在假设,过度活跃的DNA末端切除和MMEJ促进了分子水平的降低。 FA的发病机制。我们将解决以下具体目标:1)确定DNA修复途径, FA过度活跃; 2)揭示促进FA胚胎发育和发病机制; 3) 检查MMEJ抑制对FA发病机制的影响。总的来说,拟议的实验将产生 对DNA修复机制的新见解,促进基因组不稳定性和FA。

项目成果

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Neil Johnson其他文献

Neil Johnson的其他文献

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{{ truncateString('Neil Johnson', 18)}}的其他基金

Assessing DNA polymerase theta as a therapeutic target in BRCA1 mutant cancer
评估 DNA 聚合酶 θ 作为 BRCA1 突变癌症的治疗靶点
  • 批准号:
    10446399
  • 财政年份:
    2022
  • 资助金额:
    $ 46.75万
  • 项目类别:
Assessing DNA Polymerase Theta as a Therapeutic Target in BRCA1 Mutant Cancer
评估 DNA 聚合酶 Theta 作为 BRCA1 突变癌症的治疗靶点
  • 批准号:
    10884036
  • 财政年份:
    2022
  • 资助金额:
    $ 46.75万
  • 项目类别:
Assessing DNA polymerase theta as a therapeutic target in BRCA1 mutant cancer
评估 DNA 聚合酶 θ 作为 BRCA1 突变癌症的治疗靶点
  • 批准号:
    10579323
  • 财政年份:
    2022
  • 资助金额:
    $ 46.75万
  • 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
  • 批准号:
    10664883
  • 财政年份:
    2020
  • 资助金额:
    $ 46.75万
  • 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
  • 批准号:
    10229611
  • 财政年份:
    2020
  • 资助金额:
    $ 46.75万
  • 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
  • 批准号:
    10453625
  • 财政年份:
    2020
  • 资助金额:
    $ 46.75万
  • 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
  • 批准号:
    10388570
  • 财政年份:
    2020
  • 资助金额:
    $ 46.75万
  • 项目类别:
The role of microhomology-mediated end joining in Fanconi anemia pathogenesis
微同源介导的末端连接在范可尼贫血发病机制中的作用
  • 批准号:
    10367981
  • 财政年份:
    2020
  • 资助金额:
    $ 46.75万
  • 项目类别:
Compensatory mechanisms that promote homologous recombination in BRCA1 mutant cancers
促进 BRCA1 突变癌症同源重组的补偿机制
  • 批准号:
    10242152
  • 财政年份:
    2019
  • 资助金额:
    $ 46.75万
  • 项目类别:
Compensatory mechanisms that promote homologous recombination in BRCA1 mutant cancers
促进 BRCA1 突变癌症同源重组的补偿机制
  • 批准号:
    9762056
  • 财政年份:
    2019
  • 资助金额:
    $ 46.75万
  • 项目类别:

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非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
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