Bypass Mechanisms in Eukaryotic Replication

真核复制中的旁路机制

基本信息

  • 批准号:
    10500889
  • 负责人:
  • 金额:
    $ 36.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Chromosomes are copied by a complex holoenzyme called the replisome. Obstacles are routinely negotiated by the replisome with auxiliary mechanisms, collectively called DNA damage tolerance pathways, that ensure genomic integrity via on-the-fly remodeling. The aberrance of these pathways can lead to chromosome instability and a broad range of diseases including cancer. The Schauer Lab’s long-term goal is to thus understand the molecular basis for genetic and epigenetic fidelity, with the goal of improving the treatment and/or prevention of diseases. In this proposal, the Schauer Lab will use a fully functional replisome reconstituted from over 30 pure polypeptides to study how replisomes bypass obstacles that regularly occur in the genome while enforcing genetic and epigenetic integrity across generations. They also propose to develop whole cell lysate systems to establish active replication forks on double-stranded DNA at natural origins of replication without the need for replication initiation on synthetic forks. DNA damage tolerance mechanisms will be studied using biochemistry, single-molecule biophysics, and structural biology. The structural dynamics of the S-phase damage response will be characterized, with a focus on the mediator kinase Mrc1 and the multiple ways it regulates the elongating replisome. The Schauer Lab also proposes to study the spatiotemporal mechanisms of rescue of lesion-stalled replisomes by translesion synthesis polymerases, and how both Mrc1 and ubiquitination of DNA sliding clamps regulates this response. When replicating chromatin, nucleosomes present a strong block to replication fork progression in the absence of histone chaperones. The Schauer Lab will study histone dynamics at the replication fork in reconstituted chromatin, with a focus on regulation of histone deposition symmetry by histone chaperones and in the molecular mechanisms of various replication- coupled histone chaperones themselves. Tools will be developed to track histone fate and dynamics at the single-molecule level. The goal is to get a better understanding of the processes that control epigenetic inheritance, important for maintaining cellularity during cell division. Finally, the Schauer Lab proposes to study collisions between the replication machinery and an actively elongating transcription complex, since these conflicts can be highly mutagenic. Transcriptional regulation by the rpb4/7 heterodimer will also be studied. Transcription will be reconstituted from either purified proteins, or whole-cell extracts, or a combination of the two. The Schauer Lab is developing biochemical and single-molecule tools for these projects that will afford an unprecedented glimpse into the molecular mechanisms behind these critical processes. Single-molecule fluorescence resonance energy transfer (smFRET) will be employed to track intermolecular interactions, allowing a characterization of the structural dynamics of these systems. Further, technology will be developed to track dynamic motions of fluorescently labeled proteins on double-tethered DNA at the single-molecule level. The mechanistic insight afforded by these studies will be beneficial for the medical research community.
项目总结

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Grant Schauer其他文献

Grant Schauer的其他文献

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{{ truncateString('Grant Schauer', 18)}}的其他基金

Bypass Mechanisms in Eukaryotic Replication
真核复制中的旁路机制
  • 批准号:
    10672310
  • 财政年份:
    2022
  • 资助金额:
    $ 36.06万
  • 项目类别:
Bypass Mechanisms in Eukaryotic Replication
真核复制中的旁路机制
  • 批准号:
    10798784
  • 财政年份:
    2022
  • 资助金额:
    $ 36.06万
  • 项目类别:
BYPASS MECHANISMS IN EUKARYOTIC REPLICATION
真核复制中的旁路机制
  • 批准号:
    10249266
  • 财政年份:
    2018
  • 资助金额:
    $ 36.06万
  • 项目类别:
BYPASS MECHANISMS IN EUKARYOTIC REPLICATION
真核复制中的旁路机制
  • 批准号:
    10017302
  • 财政年份:
    2018
  • 资助金额:
    $ 36.06万
  • 项目类别:

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  • 财政年份:
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眼前泪膜的生物化学和生物物理学
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  • 财政年份:
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  • 资助金额:
    $ 36.06万
  • 项目类别:
Biochemistry and Biophysics of the Preocular Tear Film
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  • 批准号:
    8035889
  • 财政年份:
    2010
  • 资助金额:
    $ 36.06万
  • 项目类别:
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