DISSECTION OF A METAZOAN PRE-REPLICATION COMPLEX

后生动物复制前复合体的解剖

基本信息

  • 批准号:
    6768584
  • 负责人:
  • 金额:
    $ 23.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2000
  • 资助国家:
    美国
  • 起止时间:
    2000-07-01 至 2006-06-30
  • 项目状态:
    已结题

项目摘要

The mechanisms controlling duplication of metazoan chromosomes are only beginning to be understood. In multicellular eukaryotes, it is not known what organization of DNA sequences constitutes an origin of DNA replication, nor is it fully understood how cell cycle controls result in the firing of origins only once in a cell cycle. Based on work in yeast, the prediction is that assembly of a pre-replication complex (pre-RC) onto origins in Gl is the central control point for once per cell cycle replication. However, specific association of the pre-RC with a metazoan origin of replication has not been reported. It is also predicted that cyclin dependent kinases (CDKs), in addition to activating the pre-RC in S, also inhibit pre- RC assembly in G2 and M; however, the mechanisms underlying these dual functions are unclear. Among the best understood origins of replication in higher eukaryotes are those used for developmental amplification of eggshell (chorion) genes during Drosophila oogenesis. The regions that are critical for origin function have been mapped to less than 1Kb. Recent results indicate that chorion amplification requires CDKs, pre-RC subunits, and other molecules required for Gl/S progression. We propose to use the chorion system to study origin structure and the cell cycle regulation of preRC assembly in metazoa. To begin, we will map DNA sequences to which the pre-RC binds in relation to replication start sites, and ask how this binding is modulated in response to cell cycle regulation. Next, we will investigate the structure of the pre-RC in vivo through genetic and molecular manipulation of a gene implicated in pre-RC function. Finally, we will use modern tools of Drosophila genetics to conduct Fl genetic screens for mutations which disrupt amplification. These screens should identify the cadre of proteins associated with origins, and the regulatory pathways that control their activity. Moreover, by examining what differs between amplification and normal replication, we should gain insight into the mechanisms by which origin firing is restricted to once per cell cycle. Combined with the advantages inherent in Drosophila as a model organism, this system represents an opportunity for the genetic and molecular dissection of the cell cycle control of metazoan replication.
控制后生动物染色体复制的机制才刚刚开始被理解。在多细胞真核生物中,不知道DNA序列的什么组织构成DNA复制的起源,也不完全了解细胞周期控制如何导致在细胞周期中仅触发一次起源。基于对酵母的研究,预测一个预复制复合体(pre-RC)在Gl的起源上的组装是每个细胞周期复制一次的中心控制点。然而,pre-RC与后生动物复制起源的具体关联尚未报道。我们还预测,细胞周期蛋白依赖激酶(CDKs)除了激活S中的pre-RC外,还抑制G2和M中的pre-RC组装;然而,这些双重功能背后的机制尚不清楚。在高等真核生物中,最容易理解的复制起源是在果蝇卵发生过程中用于蛋壳(绒毛膜)基因的发育扩增。对原点功能至关重要的区域被映射到小于1Kb。最近的研究结果表明,绒毛膜扩增需要CDKs、pre-RC亚基和Gl/S进展所需的其他分子。我们建议利用绒毛膜系统来研究后生动物中prec组装的起源结构和细胞周期调控。首先,我们将绘制pre-RC结合的DNA序列与复制起始位点的关系,并询问这种结合是如何响应细胞周期调节而被调节的。接下来,我们将通过对pre-RC功能相关基因的遗传和分子操作来研究pre-RC在体内的结构。最后,我们将利用果蝇遗传学的现代工具对破坏扩增的突变进行Fl基因筛选。这些筛选应该确定与起源相关的蛋白质骨干,以及控制其活性的调节途径。此外,通过检查扩增和正常复制之间的区别,我们应该深入了解起源激活限制在每个细胞周期一次的机制。结合果蝇作为模式生物的固有优势,该系统为后生动物复制的细胞周期控制的遗传和分子解剖提供了机会。

项目成果

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BRIAN R CALVI其他文献

BRIAN R CALVI的其他文献

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{{ truncateString('BRIAN R CALVI', 18)}}的其他基金

Polypoid cell cycle regulation and genome instability
息肉样细胞周期调控和基因组不稳定性
  • 批准号:
    10410419
  • 财政年份:
    2015
  • 资助金额:
    $ 23.4万
  • 项目类别:
Polyploid cell cycle regulation and genome instability
多倍体细胞周期调控和基因组不稳定性
  • 批准号:
    9276715
  • 财政年份:
    2015
  • 资助金额:
    $ 23.4万
  • 项目类别:
Polyploid cell cycle regulation and genome instability
多倍体细胞周期调控和基因组不稳定性
  • 批准号:
    8962579
  • 财政年份:
    2015
  • 资助金额:
    $ 23.4万
  • 项目类别:
Polypoid cell cycle regulation and genome instability
息肉样细胞周期调控和基因组不稳定性
  • 批准号:
    10165740
  • 财政年份:
    2015
  • 资助金额:
    $ 23.4万
  • 项目类别:
Chromatin regulated DNA replication
染色质调控 DNA 复制
  • 批准号:
    7900636
  • 财政年份:
    2009
  • 资助金额:
    $ 23.4万
  • 项目类别:
DISSECTION OF A METAZOAN PRE-REPLICATION COMPLEX
后生动物复制前复合体的解剖
  • 批准号:
    6387158
  • 财政年份:
    2000
  • 资助金额:
    $ 23.4万
  • 项目类别:
DISSECTION OF A METAZOAN PRE-REPLICATION COMPLEX
后生动物复制前复合体的解剖
  • 批准号:
    6091794
  • 财政年份:
    2000
  • 资助金额:
    $ 23.4万
  • 项目类别:
DISSECTION OF A METAZOAN PRE-REPLICATION COMPLEX
后生动物复制前复合体的解剖
  • 批准号:
    6636453
  • 财政年份:
    2000
  • 资助金额:
    $ 23.4万
  • 项目类别:
Chromatin regulated DNA replication
染色质调控 DNA 复制
  • 批准号:
    7688558
  • 财政年份:
    2000
  • 资助金额:
    $ 23.4万
  • 项目类别:
DISSECTION OF A METAZOAN PRE-REPLICATION COMPLEX
后生动物复制前复合体的解剖
  • 批准号:
    6520248
  • 财政年份:
    2000
  • 资助金额:
    $ 23.4万
  • 项目类别:

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