G2/M DNA DAMAGE CHECKPOINT IN BUDDING YEAST

芽殖酵母中的 G2/M DNA 损伤检查点

基本信息

  • 批准号:
    2608920
  • 负责人:
  • 金额:
    $ 20.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1991
  • 资助国家:
    美国
  • 起止时间:
    1991-01-01 至 2000-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION: In eukaryotic cells, DNA damage causes arrest of the cell cycle to allow repair of this damage. A number of genes, termed "checkpoint" genes, required for this arrest have been identified in yeast and in other organisms. Human checkpoint genes include p53 and ATM and mutations in these genes are associated with increased probability of developing cancer. Dr. Weinert suggests that there may be three types of checkpoint proteins: 1) sensor proteins which bind and, perhaps, process DNA damage, 2) signal proteins that interact with the sensor protein and transduce a signal to target genes, and 3) the target genes, which directly mediate cell cycle arrest. His first series of experiments concern how sensor proteins act on DNA damage. Strains with the cdc13 mutation develop long single-stranded regions near the end of the chromosome. Dr. Weinert has found that mutations in the rad24 checkpoint gene reduced this degradation, and mutations in the rad9 checkpoint gene increased the degradation. He will determine whether the degradation occurs 3' to 5' or 5' to 3', and he will examine the effects of other mutations (for example, rad17) on the degradation process. The Rad17p shares homology with Rec1p, a known 3' to 5' exonuclease. Dr. Weinert will purify Rad17p and determine whether Rad17p is a 3' to 5' exonuclease. He will also try to localize Rad17p, Rad24 and Mec3p to sites of meiosis-specific DSB's using immunofluorescence. The point of these studies is to test the hypothesis that these proteins represent sensor proteins that process the cdc13-caused DNA damage. The second part of the proposal is designed to address two questions. First, is processing of DNA damage by Rad24p and Rad17p required to repair this DNA damage? Second, does cell cycle arrest require Rad24p and Rad17p to process the DNA damage? Dr. Weinert will try to answer these questions by mutating RAD17 and RAD24, and determining whether any of the mutant alleles show separation of function. For example, if he obtains a rad17 mutant that does not process DNA damage, but does show cell-cycle arrest, he will have demonstrated that DNA processing is not required for cell-cycle arrest. The third part of the proposal concerns new checkpoint mutants. His previous hunts involved looking for mutants that had poor viability after exposure to DNA damage. His new hunt will employ a direct search for cells that fail to show G2/M arrest in response to DNA damage. He hopes that this search will identify target genes of the checkpoint response. The last series of experiments investigate the order of function of genes in the checkpoint pathway. Dr. Weinert proposes looking at protein-protein interactions between different checkpoint proteins using the two-hybrid system or affinity columns. He also proposes two types of epistasis tests. Work from the Elledge lab suggests that the Rad53p is phosphorylated as part of the checkpoint response and functions downstream of Mec1p and the sensor proteins. Dr. Weinert will attempt to confirm this conclusion. If the conclusion is confirmed, he will determine the effect of various checkpoint mutations on the phosphorylation of Rad53p. He will also attempt to isolate a mec1 mutant with the phenotype of cold-sensitive constitutive function. He will then examine interactions with other mutants. A double mutant with a mec1 constitutive and a mutant in a gene that functions downstream of MEC1 should fail to show arrest at the restrictive temperature.
描述:在真核细胞中,DNA损伤会导致细胞停滞 循环以允许修复此损坏。一些基因,被称为 在酵母菌中鉴定出了这一过程所需的“检查点”基因。 在其他生物中也是如此。人类检查点基因包括P53和ATM以及 这些基因的突变与患病几率的增加有关。 罹患癌症。Weinert博士认为,可能有三种类型的 检查点蛋白:1)结合并可能加工的传感蛋白 DNA损伤,2)与传感器蛋白相互作用的信号蛋白和 将信号转导到靶基因,以及3)靶基因,它直接 调节细胞周期停滞。 他的第一系列实验涉及传感器蛋白如何作用于dna。 损坏。带有cdc13突变的菌株产生长单链 染色体末端附近的区域。Weinert博士发现 Rad24检查点基因的突变减少了这种降解,并且 Rad9检查点基因的突变加剧了这种退化。他会的 确定降级是发生在3‘到5’还是5‘到3’,他将 检查其他突变(例如,rad17)对 降解过程。Rad17p与Rec1p有同源性,Rec1p是已知的3‘TO 5‘端核酸外切酶。Weinert博士将提纯Rad17p并确定Rad17p 是一种3‘到5’的核酸外切酶。他还将尝试本地化Rad17p、Rad24和 用免疫荧光法将Mec3p定位于减数分裂特异的DSB位点。这个 这些研究的重点是检验这样一个假设,即这些蛋白质 代表处理cdc13引起的DNA损伤的传感器蛋白。 提案的第二部分旨在解决两个问题。 首先,是否需要对Rad24p和Rad17p造成的DNA损伤进行处理以修复 这种DNA损伤?第二,细胞周期停滞是否需要Rad24p和Rad17p 来处理DNA损伤吗?Weinert博士将尝试回答这些问题 通过突变RAD17和RAD24,并确定是否有任何突变 等位基因表现出功能的分离。例如,如果他获得了一个ra17 不处理DNA损伤,但确实显示细胞周期停滞的突变体,他说 将证明DNA处理不是细胞周期所必需的 逮捕。 提案的第三部分涉及新的检查站突变体。他的 以前的猎杀涉及寻找生存能力较差的突变体 暴露在DNA损伤中。他的新搜索将采用直接搜索细胞 没有显示出对DNA损伤的G2/M期停滞。他希望这件事 搜索将识别检查点响应的目标基因。 最后一系列实验研究了基因的功能顺序。 检查站路径。Weinert博士建议研究蛋白质--蛋白质 利用双杂交技术研究不同检查点蛋白之间的相互作用 系统或地缘性列。他还提出了两种上位性测试。 Elledge实验室的研究表明,Rad53p被磷酸化 Mec1p和传感器下游的检查点响应和功能 蛋白质。Weinert博士将尝试证实这一结论。如果 结论得到确认后,他将决定各个检查站的效果 RAD53P的磷酸化突变。他还将试图孤立 一个Mec1突变体,其表型为冷敏感的结构性功能。 然后,他将研究与其他突变体的相互作用。一个双重突变体,带有 Mec1下游功能基因中的Mec1组分和突变体 在限制的温度下不会显示出被逮捕的迹象。

项目成果

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TED A. WEINERT其他文献

TED A. WEINERT的其他文献

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{{ truncateString('TED A. WEINERT', 18)}}的其他基金

Uranium as an Environmental Risk Factor for Cancer Among the Navajo
铀是纳瓦霍人癌症的环境危险因素
  • 批准号:
    7833738
  • 财政年份:
    2009
  • 资助金额:
    $ 20.64万
  • 项目类别:
Checkpoint protein interactions with a fragile site and chromosome instability
检查点蛋白与脆弱位点的相互作用和染色体不稳定性
  • 批准号:
    7478549
  • 财政年份:
    2006
  • 资助金额:
    $ 20.64万
  • 项目类别:
Chromosome inverted fusions, dicentrics and genome instability
染色体倒置融合、双着丝粒和基因组不稳定性
  • 批准号:
    8665436
  • 财政年份:
    2006
  • 资助金额:
    $ 20.64万
  • 项目类别:
Checkpoint protein interactions with a fragile site and chromosome instability
检查点蛋白与脆弱位点的相互作用和染色体不稳定性
  • 批准号:
    7656877
  • 财政年份:
    2006
  • 资助金额:
    $ 20.64万
  • 项目类别:
Chromosome inverted fusions, dicentrics and genome instability
染色体倒置融合、双着丝粒和基因组不稳定性
  • 批准号:
    8528617
  • 财政年份:
    2006
  • 资助金额:
    $ 20.64万
  • 项目类别:
Checkpoint protein interactions with a fragile site and chromosome instability
检查点蛋白与脆弱位点的相互作用和染色体不稳定性
  • 批准号:
    7148715
  • 财政年份:
    2006
  • 资助金额:
    $ 20.64万
  • 项目类别:
Checkpoint protein interactions with a fragile site and chromosome instability
检查点蛋白与脆弱位点的相互作用和染色体不稳定性
  • 批准号:
    7261364
  • 财政年份:
    2006
  • 资助金额:
    $ 20.64万
  • 项目类别:
Chromosome inverted fusions, dicentrics and genome instability
染色体倒置融合、双着丝粒和基因组不稳定性
  • 批准号:
    8373321
  • 财政年份:
    2006
  • 资助金额:
    $ 20.64万
  • 项目类别:
G2/M DNA DAMAGE CHECKPOINT IN BUDDING YEAST
芽殖酵母中的 G2/M DNA 损伤检查点
  • 批准号:
    6125409
  • 财政年份:
    1991
  • 资助金额:
    $ 20.64万
  • 项目类别:
G2/M DNA DAMAGE CHECKPOINT IN BUDDING YEAST
芽殖酵母中的 G2/M DNA 损伤检查点
  • 批准号:
    2022428
  • 财政年份:
    1991
  • 资助金额:
    $ 20.64万
  • 项目类别:

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