Biochemistry of recombination in gametogenesis

配子发生重组的生物化学

基本信息

  • 批准号:
    7629562
  • 负责人:
  • 金额:
    $ 27.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-08-10 至 2011-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Meiosis, a central part of gametogenesis, is essential for sexual reproduction. In meiosis chromosomes replicate once, then segregate twice to produce haploid meiotic products. A conserved, meiosis-specific homologous recombination pathway ensures the proper segregation of chromosomes in meiosis I. Complete loss of recombination triggers apoptosis during gametogenesis and, hence, sterility. Thus, meiotic recombination is a candidate target for reversible, pre-fertilization, male contraceptives. Recombination is initiated by double-strand DMA (dsDNA) breaks induced in meiotic prophase. Many genes are required for formation of dsDNA breaks in vivo, but little is known about their respective proteins. One of the proteins, Red 2 (Spoil), is orthologous to the catalytic subunit of type MB topoisomerases and is implicated to catalyze formation of recombinogenic dsDNA breaks. Although this implication was made about ten years ago, no in vitro activities of the protein have been reported. We report that Red 2, its putative active site tyrosine, and a DNA binding motif are essential for recombination. We purified a Rec12-associated complex that contains six proteins known to be required for meiotic recombination and four proteins with inferred biochemical activities of recombination. We also purified recombinant Red 2 expressed from two different sources (bacteria, vegetative yeast cells). The meiotic protein complex and each preparation of purified Red 2 can cleave dsDNA in vitro. Amino acid substitutions affecting specifically DNA binding or catalysis can be distinguished in vitro. The focus for this period is upon the biochemistry of Red 2 and associated proteins. The specific aims are: (1) To determine biochemical mechanisms by which Red 2 binds to and cleaves DNA. (2) To identify key residues of Red 2 essential for functions in vivo and in vitro. (3) To determine the composition of a Red 2 protein complex from meiosis. (4) To develop in vitro assays for high- throughput screening of potential anti-Red 2 compounds. The results will reveal conserved proteins of potential diagnostic value for defects in human reproductive biology. They will also pave the way for rational drug design and high-throughput screening to identify potential contraceptive agents that affect specifically Rec12-dependent function, thereby triggering meiosis-specific apoptosis without adverse side-effects on somatic tissues.
描述(申请人提供):减数分裂是配子发生的核心部分,是有性生殖的必要条件。在减数分裂中,染色体复制一次,然后分离两次,产生单倍体减数分裂产物。一个保守的、减数分裂特异性的同源重组途径确保了减数分裂i中染色体的适当分离。重组的完全丧失会在配子体发生过程中引发细胞凋亡,从而导致不育。因此,减数分裂重组是可逆的,受精前,男性避孕药的候选目标。重组是由减数分裂前期诱导的双链DMA (dsDNA)断裂引发的。许多基因需要在体内形成dsDNA断裂,但对它们各自的蛋白质知之甚少。其中一种蛋白质,Red 2 (Spoil),与MB型拓扑异构酶的催化亚基同源,与催化重组dna断裂的形成有关。虽然这一结论是在大约十年前提出的,但没有关于该蛋白体外活性的报道。我们报道红2,其假定的活性位点酪氨酸和DNA结合基序是重组所必需的。我们纯化了一个与rec12相关的复合体,该复合体包含六种已知的减数分裂重组所需的蛋白质和四种推断具有重组生化活性的蛋白质。我们还纯化了从两种不同来源(细菌和营养酵母细胞)表达的重组红2。减数分裂蛋白复合体和纯化红2的各制剂均能在体外切割dsDNA。氨基酸取代影响特异性DNA结合或催化可以在体外区分。这一时期的焦点是红2和相关蛋白质的生物化学。具体目的是:(1)确定Red 2结合和切割DNA的生化机制。(2)在体内和体外鉴定Red 2的关键功能残基。(3)测定减数分裂中红2蛋白复合体的组成。(4)建立高通量筛选潜在抗红2化合物的体外检测方法。结果将揭示对人类生殖生物学缺陷具有潜在诊断价值的保守蛋白。它们还将为合理的药物设计和高通量筛选铺平道路,以确定潜在的避孕药,这些避孕药特异性影响rec12依赖的功能,从而触发减数分裂特异性凋亡,而不会对体细胞组织产生不良副作用。

项目成果

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Wayne P Wahls其他文献

Wayne P Wahls的其他文献

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{{ truncateString('Wayne P Wahls', 18)}}的其他基金

Systematic elucidation of DNA sequence codes that regulate meiotic recombination
系统阐明调节减数分裂重组的 DNA 序列代码
  • 批准号:
    10618255
  • 财政年份:
    2022
  • 资助金额:
    $ 27.55万
  • 项目类别:
Systematic elucidation of DNA sequence codes that regulate meiotic recombination
系统阐明调节减数分裂重组的 DNA 序列代码
  • 批准号:
    10418872
  • 财政年份:
    2022
  • 资助金额:
    $ 27.55万
  • 项目类别:
Biochemistry of recombination in gametogenesis
配子发生重组的生物化学
  • 批准号:
    7896253
  • 财政年份:
    2009
  • 资助金额:
    $ 27.55万
  • 项目类别:
Biochemistry of recombination in gametogenesis
配子发生重组的生物化学
  • 批准号:
    7871352
  • 财政年份:
    2007
  • 资助金额:
    $ 27.55万
  • 项目类别:
Biochemistry of recombination in gametogenesis
配子发生重组的生物化学
  • 批准号:
    7479809
  • 财政年份:
    2007
  • 资助金额:
    $ 27.55万
  • 项目类别:
Biochemistry of recombination in gametogenesis
配子发生重组的生物化学
  • 批准号:
    7302820
  • 财政年份:
    2007
  • 资助金额:
    $ 27.55万
  • 项目类别:
Biochemistry of recombination in meiosis
减数分裂重组的生物化学
  • 批准号:
    8961476
  • 财政年份:
    2007
  • 资助金额:
    $ 27.55万
  • 项目类别:
Combinatoial CREB/ATF dimers and cellular growth control
CREB/ATF二聚体组合和细胞生长控制
  • 批准号:
    6775629
  • 财政年份:
    2001
  • 资助金额:
    $ 27.55万
  • 项目类别:
REGULATION OF MEIOTIC DEVELOPMENT BY MTS1-MTS2 PROTEIN
MTS1-MTS2 蛋白对减数分裂发育的调节
  • 批准号:
    6227514
  • 财政年份:
    2001
  • 资助金额:
    $ 27.55万
  • 项目类别:
REGULATION OF MEIOTIC DEVELOPMENT BY MTS1-MTS2 PROTEIN
MTS1-MTS2 蛋白对减数分裂发育的调节
  • 批准号:
    6628931
  • 财政年份:
    2001
  • 资助金额:
    $ 27.55万
  • 项目类别:

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