Structure, mechanism, and function of the histone chaperones Spt6 and FACT

组蛋白伴侣 Spt6 和 FACT 的结构、机制和功能

基本信息

  • 批准号:
    9265478
  • 负责人:
  • 金额:
    $ 29.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-05-01 至 2020-04-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): This proposal focuses on Spt6 (168 kDa) and FACT, which is a heterodimer of Spt16 (119 kDa) and Pob3 (63 kDa). Spt6 and FACT are histone chaperones that are conserved throughout eukaryotes, implicated in HIV latency and other disease processes, and unlike most structurally characterized histone chaperones, are essential for viability. Both Spt6 and FACT function in the assembly of nucleosomes, which is required as the DNA is doubled during replication in S phase and also to replace nucleosomes that become irretrievably displaced by remodeling or by passage of an RNA polymerase during transcription. FACT also reorganizes nucleosomes, forming a loosened structure that promotes passage of RNA polymerase but maintains contacts with each of the components so that the same displaced histone molecules are incorporated back into the reconstructed nucleosome. Our collaboration has previously produced multiple structures of domains of Spt6, a complex of Spt6 with the essential factor Spn1, and multiple structures of domains of the FACT heterodimer. We also performed genetic and binding studies that validated the biological importance of these structures and advanced understanding of mechanisms. We will continue this multidisciplinary approach, which is essential for making meaningful progress in this challenging field. An important priority in Aims 1 and 2 is to biochemically and structurally characterize interactions with histones, which are fundamental to Spt6 and FACT function. We favor the model that Spt6 and FACT function in large part by covering histone surfaces that otherwise associate with DNA or other histones in the nucleosome structure, and we therefore believe that biochemically understanding these interactions and verifying their biological importance will reveal the primary basis of Spt6 and FACT activities in loosening and assembling nucleosomes. Histones are notoriously challenging subjects for binding studies, and our multidisciplinary approach, which includes rigorous biochemistry, places us in an excellent position to pursue high impact goals and has already led to an insightful preliminary FACT:H2A-H2B crystal structure. Specific hypotheses generated from the insights provided by Aims 1 and 2 are driving functional studies that are being pursued for Spt6 in Aim 3, including the mechanistic and physiological role of the Spn1 binding partner. Aim 4 is advancing the important but understudied question of how the essential histone chaperones are coupled to diverse biological pathways. Specifically, we have discovered that Spt6 binds directly and specifically with RNA polymerase II (RNAPII) and with Tom1. These interactions presumably underlie Spt6's distinct roles in transcription elongation and mRNA export, respectively, and the Tom1 interaction further implicates Spt6 in the maintenance of histone homeostasis and has ramifications for understanding certain forms of hepatocellular carcinoma and mental impairment in humans. Preliminary data include an initial EM structure of the RNAPII-Spt6 complex, identification of Spt6 point mutants that specifically disrupt binding to RNAPII or to Tom1, and identification of a phosphorylation- dependent switch for binding to RNAPII.
 描述(由申请人提供):该提案重点介绍SPT6(168 kDa)和事实,这是SPT16的异二聚体(119 kDa),而事实是组蛋白伴侣,是保守的Throghout Euckaryotes与大多数结构化的组蛋白伴侣在核小体组装中的作用不同,这是在s相中复制过程中需要加倍的,并且要替代通过转录过程中ANA聚合酶通过ANA聚合酶的不可挽回的核类。在每个组件中,将相同的遥远分子掺入重建的核校化中,以前产生了SPT6 TOR SPN1的域的多个结构,而FACT HETRODIMER的多个结构也进行了遗传。这些结构和对机制的高级理解,我们将继续对有意义的计划进行饮食。从生物化学上,这些相互作用和验证其生物周围的重要性将是SPT6的主要基础,而臭素蛋白酶却是臭名昭著的。影响目标,已经导致了有见地的预序:H2A-H2B的晶体结构在AIM 3中进行,包括SPN1结合伙伴的机械和生理作用。 SPT6直接与RNA聚合酶II(RNAPII)和TOM1结合。人类的静态精神。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Timothy G Formosa其他文献

Timothy G Formosa的其他文献

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{{ truncateString('Timothy G Formosa', 18)}}的其他基金

QUESTION OR TRAINING REQUEST FOR THE YEAST RESOURCE CENTER
对酵母资源中心的问题或培训请求
  • 批准号:
    7957701
  • 财政年份:
    2009
  • 资助金额:
    $ 29.9万
  • 项目类别:
Biochemical & Genetic Analysis of Yeast SPN
生化
  • 批准号:
    6850813
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Biochemical and Genetic Analysis of yFACT, A Novel Nucleosome Reorganizing Factor
新型核小体重组因子 yFACT 的生化和遗传分析
  • 批准号:
    7148488
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Biochemical and Genetic Analysis of yFACT, A Novel Nucleosome Reorganizing Factor
新型核小体重组因子 yFACT 的生化和遗传分析
  • 批准号:
    8450938
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Biochemical, Genetic, and Genomic Analysis of Nucleosome Reorganization by FACT
通过 FACT 进行核小体重组的生化、遗传学和基因组分析
  • 批准号:
    9908077
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Biochemical and Genetic Analysis of yFACT, A Novel Nucleosome Reorganizing Factor
新型核小体重组因子 yFACT 的生化和遗传分析
  • 批准号:
    7254753
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Biochemical and Genetic Analysis of yFACT, A Novel Nucleosome Reorganizing Factor
新型核小体重组因子 yFACT 的生化和遗传分析
  • 批准号:
    7641050
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Biochemical and Genetic Analysis of yFACT, A Novel Nucleosome Reorganizing Factor
新型核小体重组因子 yFACT 的生化和遗传分析
  • 批准号:
    9038371
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Biochemical, Genetic, and Genomic Analysis of Nucleosome Reorganization by FACT
通过 FACT 进行核小体重组的生化、遗传学和基因组分析
  • 批准号:
    9756636
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Biochemical and Genetic Analysis of yFACT, A Novel Nucleosome Reorganizing Factor
新型核小体重组因子 yFACT 的生化和遗传分析
  • 批准号:
    8241952
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:

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