Characterizing the mechanism of the INO80 family chromatin remodeling machine

表征 INO80 系列染色质重塑机的机制

基本信息

项目摘要

Project Summary DNA encodes the genetic material to instruct all cellular process and to establish cellular identity. Cellular identity is established by both genetic content and regulation of gene expression. Gene expression is regulated by many factors including chromatin structure in eukaryotes. Chromatin structure consists of nucleosomes, comprised of ~150 bp DNA wrapped around a histone octamer. This structure regulates several DNA dependent processes including transcription and DNA damage repair. Understanding the mechanisms that regulate chromatin structure is key to understanding how biological systems are controlled in the cell. DNA dependent cellular process are known to be regulated by chromatin remodelers. Chromatin remodelers couple the energy of ATP hydrolysis to slide nucleosomes, transfer histones, and/or distort the octamer— activities that are essential to regulate the chromatin state. A unique chromatin remodeler, INO80, requires both the DEAD family ATPase and accessory subunits to slide mononucleosomes in vitro. In vivo, INO80 plays a role in both transcription and DNA damage repairs. However, it is unclear how INO80 sliding activity contributes to its diverse biological roles. Recent work from our lab revealed the following about the INO80 mechanism: (1) INO80 is regulated by two nucleosome cues: flanking DNA length and an acidic patch on histones; (2) INO80 remodeling reaction has at least one intermediate state and transition between this intermediate to a sliding product is regulated by DNA length; (3) the Nhp10 accessory module regulates the transition between intermediate state and sliding activity. With these findings, I hypothesize that INO80 senses various nucleosome cues through the accessory subunits and that these interactions contribute to the kinetic steps of a INO80 remodeling reaction. I also hypothesize that distributing the regulation of INO80 across different nucleosome cues and accessory subunits allows INO80 to respond accordingly to nucleosome cues specific to various biological contexts. This research will first investigate the intermediate nucleosome states generated by INO80 remodeling and investigate the coordination between nucleosome substrate cues and accessory modules in regulating the kinetic steps in INO80 reaction. I specifically aim to (1) determine the intermediate nucleosome structures generated by INO80; (2) determine how the intermediate step of flanking DNA unpeeling regulates the INO80 reaction; (3) determine how INO80 accessory modules regulate the ability of INO80 to sense and respond to flanking DNA length; and (4) determine how the INO80 accessory modules regulate the ability of INO80 to sense and respond to histone cues.
项目摘要 DNA对遗传物质进行编码,以指导所有细胞过程并建立细胞身份。蜂窝 同一性是通过基因含量和基因表达调控来建立的。基因表达受调控 受多种因素影响,包括真核生物中的染色质结构。染色质结构由核小体组成, 由包裹在组蛋白八聚体周围的约150个碱基的DNA组成。这种结构调节着几种DNA 依赖的过程,包括转录和DNA损伤修复。了解以下机制 调节染色质结构是理解生物系统如何在细胞中被控制的关键。 已知DNA依赖的细胞过程受染色质重构体的调控。染色质重构体 将ATP水解的能量耦合到滑动核小体、转移组蛋白和/或扭曲八聚体- 对调节染色质状态至关重要的活动。一种独特的染色质重构器INO80需要 在体外,死亡的家族ATPase和附属亚基都能滑动单核小体。在体内,INO80发挥作用 在转录和DNA损伤修复中都起到了作用。然而,目前还不清楚INO80的活动如何下滑 有助于发挥其不同的生物学作用。我们实验室最近的工作揭示了以下关于INO80的信息 机制:(1)INO80受两条核小体信号的调控:DNA长度两侧和其上的酸性斑块 组蛋白;(2)INO80重塑反应至少有一种中间状态和在这两种状态之间的过渡 滑动产物的中间受DNA长度调节;(3)Nhp10附件模块调节 中间状态和滑动活动之间的转换。根据这些发现,我假设INO80感觉到 不同的核小体信号通过辅助亚基,这些相互作用有助于动力学 INO80重塑反应的步骤。我还假设,将INO80的调控分布在 不同的核小体信号和辅助亚基使INO80对核小体信号做出相应的反应 特定于不同的生物环境。这项研究将首先研究核小体的中间状态 由INO80重塑产生,并研究核小体底物信号与 调控INO80反应动力学步骤的辅助模块。我的具体目标是(1)确定 由INO80产生的中间核小体结构;(2)决定了中间步骤如何 侧翼DNA的剥离调节INO80反应;(3)确定INO80辅助模块如何 调节INO80对侧翼DNA长度的感知和反应能力;以及(4)确定 INO80辅助模块调节INO80对组蛋白提示的感知和反应能力。

项目成果

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Muryam A.A. Gourdet其他文献

Muryam A.A. Gourdet的其他文献

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{{ truncateString('Muryam A.A. Gourdet', 18)}}的其他基金

Characterizing the mechanism of the INO80 family chromatin remodeling machine
表征 INO80 系列染色质重塑机的机制
  • 批准号:
    10424783
  • 财政年份:
    2021
  • 资助金额:
    $ 3.73万
  • 项目类别:
Supplement Characterizing the mechanism of the INO80 family chromatin remodeling machine
补充描述 INO80 系列染色质重塑机的机制
  • 批准号:
    10558103
  • 财政年份:
    2020
  • 资助金额:
    $ 3.73万
  • 项目类别:
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