Chromatin-modifying functions of INO80 in the preservation of genomic integrity

INO80 在保护基因组完整性中的染色质修饰功能

基本信息

  • 批准号:
    7845369
  • 负责人:
  • 金额:
    $ 24.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-07-04 至 2012-05-31
  • 项目状态:
    已结题

项目摘要

ATP-dependent chromatin-remodeling complexes, such as the evolutionarily-conserved INO80 complex, are essential for the maintenance of genomic integrity. However, the diverse INO80 chromatin-modifying activities that are necessary for proper DNA damage responses remain to be elucidated. Our long-term goal is to delineate the involvement of chromatin-modifying complexes in DNA damage response pathways, as well as their role in preventing disease progression through the maintenance of genomic integrity. The overall objective of this proposal, which is an initial step to the achievement of our long-term goal, utilizes the yeast model system to determine the specific involvement ofthe INO80 chromatin-remodeling complex in different functions of DNA damage response pathways. Our central hypothesis is that specific INO80 subunits contribute to critical functions in diverse genome maintenance pathways by modulating the chromatin-modifying activities of the complex. Once these objectives are accomplished, the results will provide the foundation to investigate the role of evolutionarily-conserved chromatin-remodeling complexes in disorders caused by defects in DNA damage response pathways, such as cancer. Guided by strong preliminary data, this hypothesis will be tested through an integrated experimental approach that utilizes proteomics, high-throughput genetic screens, genome-wide nucleosome mapping, and biochemical assays. We propose to test our central hypothesis and accomplish the objectives ofthis application by pursuing the following specific aims: 1) Characterize INO80 subunits that function in DNA damage responses and modulate DNA damage-specific chromatin substrates; 2) Delineate the in vitro chromatin-modifying contributions of DNA damage-related subunits to the activity INO80 complex; 3) Determine the in vivo chromatin-modifying function of INO80 subunits in specific DNA damage response pathways. These analyses are relevant to public heaith because they will provide a platform to address the potential role of INO80 in the development of disease. Ultimately, these studies will dramatically broaden our understanding of chromatin modulation that functions to preserve DNA integrity.
ATP 依赖性染色质重塑复合物,例如进化保守的 INO80 复合物, 对于维持基因组完整性至关重要。然而,多样化的 INO80 染色质修饰 适当的 DNA 损伤反应所需的活性仍有待阐明。我们的长期目标 旨在描述染色质修饰复合物在 DNA 损伤反应途径中的参与,如 以及它们通过维持基因组完整性来预防疾病进展的作用。这 该提案的总体目标是实现我们长期目标的第一步,利用 酵母模型系统,以确定 INO80 染色质重塑复合物的具体参与 DNA损伤反应途径的不同功能。我们的中心假设是特定的 INO80 亚基通过调节不同基因组维护途径中的关键功能 复合物的染色质修饰活性。一旦这些目标实现,结果将 为研究进化保守的染色质重塑复合物的作用提供基础 由 DNA 损伤反应途径缺陷引起的疾病,例如癌症。强者引导 初步数据,该假设将通过综合实验方法进行检验,该方法利用 蛋白质组学、高通量遗传筛选、全基因组核小体作图和生化测定。 我们建议通过追求以下具体目标来测试我们的中心假设并实现本申请的目标:1)表征在 DNA 损伤反应中发挥作用并调节 DNA 损伤特异性染色质底物的 INO80 亚基; 2) 描述 DNA 损伤相关亚基对 INO80 复合物活性的体外染色质修饰贡献; 3)确定INO80亚基在特定DNA损伤反应途径中的体内染色质修饰功能。这些分析与公共卫生相关,因为它们将提供一个平台来探讨 INO80 在疾病发展中的潜在作用。最终,这些研究将极大地拓宽我们对维持 DNA 完整性的染色质调节的理解。

项目成果

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Ashby J. Morrison其他文献

INO80 Chromatin Remodelling Coordinates Metabolic Homeostasis with Cell Division
INO80 染色质重塑协调代谢稳态与细胞分裂
  • DOI:
    10.1101/169128
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Graeme J. Gowans;Alicia N. Schep;Ka Man Wong;Devin A. King;W. Greenleaf;Ashby J. Morrison
  • 通讯作者:
    Ashby J. Morrison
The Yeast INO 80 Complex Operates as a Tunable DNA Length-Sensitive Switch to Regulate Nucleosome Sliding Graphical
酵母 INO 80 复合物作为可调节 DNA 长度敏感开关来调节核小体滑动图形
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Y. Zhou;Stephanie L. Johnson;Laura J Lee;Adam D. Longhurst;Sean L. Beckwith;Matthew J. Johnson;Ashby J. Morrison;G. Narlikar
  • 通讯作者:
    G. Narlikar
Process-specific somatic mutation distributions vary with three-dimensional genome structure
过程特异性体细胞突变分布随三维基因组结构而变化
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    K. Akdemir;Victoria T. Le;S. Killcoyne;Devin A. King;Ya;Yanyan Tian;Akire Inoue;S. Amin;Frederick S. Robinson;R. Herrera;E. Lynn;Kin Chan;S. Seth;L. Klimczak;M. Gerstung;D. Gordenin;John O’Brien;Lei Li;R. Verhaak;P. Campbell;R. Fitzgerald;Ashby J. Morrison;Jesse R. Dixon;A. Futreal
  • 通讯作者:
    A. Futreal
Chromatin Responses to DNA Damage
染色质对 DNA 损伤的反应
  • DOI:
  • 发表时间:
    2008
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Xuetong Shen;Ashby J. Morrison
  • 通讯作者:
    Ashby J. Morrison
Chromatin modifications in DNA repair.
DNA 修复中的染色质修饰。

Ashby J. Morrison的其他文献

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{{ truncateString('Ashby J. Morrison', 18)}}的其他基金

Origins of Genome Instability in Progeria
早衰症基因组不稳定的起源
  • 批准号:
    10162466
  • 财政年份:
    2020
  • 资助金额:
    $ 24.9万
  • 项目类别:
Origins of Genome Instability in Progeria
早衰症基因组不稳定的起源
  • 批准号:
    9979662
  • 财政年份:
    2020
  • 资助金额:
    $ 24.9万
  • 项目类别:
The Role of Chromatin in Metabolic Homeostasis
染色质在代谢稳态中的作用
  • 批准号:
    10409722
  • 财政年份:
    2016
  • 资助金额:
    $ 24.9万
  • 项目类别:
The Role of Chromatin in Metabolic Homeostasis Supplemental
染色质在代谢稳态中的作用补充剂
  • 批准号:
    10797761
  • 财政年份:
    2016
  • 资助金额:
    $ 24.9万
  • 项目类别:
The Role of Chromatin in Metabolic Homeostasis
染色质在代谢稳态中的作用
  • 批准号:
    10205189
  • 财政年份:
    2016
  • 资助金额:
    $ 24.9万
  • 项目类别:
The Role of Chromatin in Metabolic Homeostasis
染色质在代谢稳态中的作用
  • 批准号:
    9983876
  • 财政年份:
    2016
  • 资助金额:
    $ 24.9万
  • 项目类别:
The Role of Chromatin in Metabolic Homeostasis
染色质在代谢稳态中的作用
  • 批准号:
    9483315
  • 财政年份:
    2016
  • 资助金额:
    $ 24.9万
  • 项目类别:
The Role of Chromatin in Metabolic Homeostasis
染色质在代谢稳态中的作用
  • 批准号:
    10629441
  • 财政年份:
    2016
  • 资助金额:
    $ 24.9万
  • 项目类别:
The Influence of Myc on Chromatin and Genome Stability during Carcinogenesis
Myc 在癌变过程中对染色质和基因组稳定性的影响
  • 批准号:
    8584839
  • 财政年份:
    2013
  • 资助金额:
    $ 24.9万
  • 项目类别:
The Influence of Chromatin Structure on Carcinogen Susceptibility
染色质结构对致癌物易感性的影响
  • 批准号:
    8569954
  • 财政年份:
    2013
  • 资助金额:
    $ 24.9万
  • 项目类别:

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