Regulation of Replication Checkpoint by Proteolysis

蛋白水解调节复制检查点

基本信息

  • 批准号:
    7483524
  • 负责人:
  • 金额:
    $ 21.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-06-25 至 2009-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The broad and long term objectives of this proposal are to elucidate the molecular mechanisms that regulate genome stability in the cell cycle. Alteration of genome stability is a hallmark of human cancer. Cancer is often associated with polyploidy, aneuploidy and gene amplification. These genomic alterations allow cancer cells to proliferate under conditions that normal cells cannot. Recent studies suggest that replication is precisely regulated by the cell cycle to occur only once per cell cycle. Many lines of evidence indicate that replication licensing is critical for the control of re-replication and therefore genome reduplicatoin. In the cell cycle, the pre-replication complex (Pre-RC) assembles onto the replication origins at the end of mitosis and during G1 to potentiate chromatin duplication in S phase. The initial step for Pre-Rc assembly is the binding of the origin recognition complex (ORC) to the origins. CDC6 and CDT1 then associate with ORC to promote the loading of the MCM2-7 proteins. We have previously found that loss of either cyclin A or geminin, a replication inhibitor that binds to the replication licensing factor CDT1, induces accumulation of polyploid cells containing DNA content between 4N and 8N. In this application, we propose to investigate our new finding that CDT1 serves as a direct checkpoint target in response to DNA damage. We found that CDT1 is proteolyzed within minutes in response to gamma-irradiation. We have provided genetic and biochemical evidence indicating this checkpoint control represents a new checkpoint pathway independent of ATM/CHK2 and replication. We also present evidence for the involvement of an uncharacterized ubiquitin E3 ligase complex that targets CDT1 for ubiquitin-dependent degradation. We propose to investigate this new checkpoint. Our specific aims are: 1) To determine the signal that causes CDT1 degradation in response to DNA damage. 2) To isolate the new E3 ligase complex. 3) To recapitulate the CDT1 degradation in vitro. 4) To examine the cell cycle regulation of CDT1 by ubiquitin-dependent proteolysis. Since CDT1 is a critical regulator for replication licensing, understanding of its regulation should provide novel insight into the mechanism for genome stability.
描述(由申请人提供):本提案的广泛和长期目标是阐明在细胞周期中调节基因组稳定性的分子机制。基因组稳定性的改变是人类癌症的一个标志。癌症通常与多倍体、非整倍体和基因扩增有关。这些基因的改变使癌细胞能够在正常细胞不能的条件下增殖。最近的研究表明,复制受细胞周期的精确调控,每个细胞周期只发生一次。许多证据表明,复制许可对于控制再复制和基因组复制至关重要。在细胞周期中,预复制复合体(pre-replication complex, Pre-RC)在有丝分裂末期和G1期组装到复制起点上,以增强S期的染色质复制。Pre-Rc组装的第一步是将原点识别复合体(ORC)与原点结合。然后CDC6和CDT1与ORC结合,促进MCM2-7蛋白的装载。我们之前已经发现,细胞周期蛋白A或双链蛋白(一种结合复制许可因子CDT1的复制抑制剂)的缺失会诱导含有4N和8N之间DNA含量的多倍体细胞的积累。在这个应用中,我们建议研究我们的新发现,CDT1作为DNA损伤反应的直接检查点靶点。我们发现CDT1在几分钟内响应于γ辐射被蛋白水解。我们提供的遗传和生化证据表明,这种检查点控制代表了一种独立于ATM/CHK2和复制的新的检查点途径。我们也提出证据表明,一种未表征的泛素E3连接酶复合物参与了靶向CDT1的泛素依赖性降解。我们建议调查这个新的检查点。我们的具体目标是:1)确定导致CDT1降解以响应DNA损伤的信号。2)分离新的E3连接酶复合物。3)总结体外CDT1的降解。4)研究泛素依赖性蛋白水解对CDT1细胞周期的调节作用。由于CDT1是复制许可的关键调控因子,对其调控的理解将为基因组稳定性的机制提供新的见解。

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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HUI ZHANG其他文献

HUI ZHANG的其他文献

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{{ truncateString('HUI ZHANG', 18)}}的其他基金

Synaptic Dysfunction and Energy Failure in Parkinson's Disease
帕金森病的突触功能障碍和能量衰竭
  • 批准号:
    10891269
  • 财政年份:
    2022
  • 资助金额:
    $ 21.04万
  • 项目类别:
Synaptic Dysfunction and Energy Failure in Parkinson's Disease
帕金森病的突触功能障碍和能量衰竭
  • 批准号:
    10504365
  • 财政年份:
    2022
  • 资助金额:
    $ 21.04万
  • 项目类别:
Regulation of SOX Proteins by Methylation-dependent Proteolysis in Stem Cells and Development
干细胞和发育中甲基化依赖性蛋白水解对 SOX 蛋白的调节
  • 批准号:
    10531566
  • 财政年份:
    2020
  • 资助金额:
    $ 21.04万
  • 项目类别:
Regulation of SOX Proteins by Methylation-dependent Proteolysis in Stem Cells and Development
干细胞和发育中甲基化依赖性蛋白水解对 SOX 蛋白的调节
  • 批准号:
    10308399
  • 财政年份:
    2020
  • 资助金额:
    $ 21.04万
  • 项目类别:
Supplement: Regulation of SOX Proteins by Methylation-dependent Proteolysis in Stem Cells and Development
补充:干细胞和发育中甲基化依赖性蛋白水解作用对 SOX 蛋白的调节
  • 批准号:
    10810083
  • 财政年份:
    2020
  • 资助金额:
    $ 21.04万
  • 项目类别:
Elucidating Aberrant Dopamine Release in Schizophrenia
阐明精神分裂症中多巴胺的异常释放
  • 批准号:
    7871680
  • 财政年份:
    2010
  • 资助金额:
    $ 21.04万
  • 项目类别:
Elucidating Aberrant Dopamine Release in Schizophrenia
阐明精神分裂症中多巴胺的异常释放
  • 批准号:
    8055400
  • 财政年份:
    2010
  • 资助金额:
    $ 21.04万
  • 项目类别:
Regulation of Replication Checkpoint by Proteolysis
蛋白水解调节复制检查点
  • 批准号:
    7066587
  • 财政年份:
    2004
  • 资助金额:
    $ 21.04万
  • 项目类别:
Regulation of Replication Checkpoint by Proteolysis
蛋白水解调节复制检查点
  • 批准号:
    7236706
  • 财政年份:
    2004
  • 资助金额:
    $ 21.04万
  • 项目类别:
Regulation of Replication Checkpoint by Proteolysis
蛋白水解调节复制检查点
  • 批准号:
    6777947
  • 财政年份:
    2004
  • 资助金额:
    $ 21.04万
  • 项目类别:

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