Homology Directed Repair

同源定向修复

基本信息

项目摘要

Rad51 protein is the eukaryotic representative of the RecA/Rad51 fannlly of DNA strand transferase enzymes. Homologous DNA strand exchanges catalyzed by RadSI are critical for Homology-Dlrected DNA Repair (HDR) and therefore for genome stability. To promote HDR, RadSI must first assemble onto single stranded DNA In the form of a presynaptic filament. Filament assembly allosterically activates RadSI to catalyze ATP hydrolysis, to search for homology in a sister chromosome, and to perform DNA strand exchange reactions. There Is compelling evidence that defects in the assembly and activity of RadSI presynaptic filaments are linked to human cancer. The overall goal of Project 3 Is to understand how specific changes in the structure, function, and molecular interactions of RadSI can lead to genomic instability and cancer. The SPECIFIC AIMS of Project 3 are: (1) To test the hypothesis that key amino acid residues at the filament interface and in the ATPase active site of RadSI control the allosteric transitions that couple the ATPase catalytic cycle to DNA strand exchange. Using yeast RadSI as a model, the catalytic and allosteric mechanisms of RadSI will be probed using a combination of site-directed mutagenesis, biochemical and biophysical analyses, and structural biology methods. (2) To test the hypothesis that tumor-derived variants of human hRADSI protein have altered biochemical and/or regulatory properties. hRADSI variants identified in Project 1 will be characterized biochemically alongside wild-type hRADSI to identify any changes in DNA binding or catalytic properties, or in key protein-protein interactions. (3) To test the hypothesis that interactions between hRADSI and DNA polymerase beta (Pol-beta) help recruit hRADSI onto ssDNA generated as a result of abortive base excision repair (BER). hRADSI:Pol-beta interactions will be characterized biochemically and disrupted by mutagenesis to assess their importance for DNA repair functions. Interesting mutants from Aims 2-3 will be exported to Projects 1 and 4 for in vivo and chromatin studies. This project will provide rigorous models for the structure, function, and assembly of RadSI presynaptic filaments, and for potential cross-talk between HDR and BER pathways, in normal vs, tumor cells, which will be useful for predicting cancer susceptibility and for developing new cancer treatments.
Rad51蛋白是DNA链转移酶RecA/Rad51系列的真核代表

项目成果

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SCOTT W MORRICAL其他文献

SCOTT W MORRICAL的其他文献

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{{ truncateString('SCOTT W MORRICAL', 18)}}的其他基金

STRUCTURE AND FUNCTION OF HOMOLOGOUS RECOMBINATION ENZYMES
同源重组酶的结构和功能
  • 批准号:
    6997980
  • 财政年份:
    2004
  • 资助金额:
    $ 19.64万
  • 项目类别:
Homology Directed Repair
同源定向修复
  • 批准号:
    8381905
  • 财政年份:
    2004
  • 资助金额:
    $ 19.64万
  • 项目类别:
Homology Directed Repair
同源定向修复
  • 批准号:
    8725060
  • 财政年份:
    2004
  • 资助金额:
    $ 19.64万
  • 项目类别:
Homology Directed Repair
同源定向修复
  • 批准号:
    8543550
  • 财政年份:
    2004
  • 资助金额:
    $ 19.64万
  • 项目类别:
Homology Directed Repair
同源定向修复
  • 批准号:
    7992616
  • 财政年份:
    2004
  • 资助金额:
    $ 19.64万
  • 项目类别:
ASSEMBLY AND ACTIVATION OF ENZYME SSDNA COMPLEXES
SSDNA 酶复合物的组装和激活
  • 批准号:
    2396916
  • 财政年份:
    1996
  • 资助金额:
    $ 19.64万
  • 项目类别:
Assembly and Activation of Enzyme-ssDNA Complexes
酶-ssDNA复合物的组装和激活
  • 批准号:
    6544460
  • 财政年份:
    1993
  • 资助金额:
    $ 19.64万
  • 项目类别:
Assembly and Activation of Enzyme-ssDNA Complexes
酶-ssDNA复合物的组装和激活
  • 批准号:
    6920725
  • 财政年份:
    1993
  • 资助金额:
    $ 19.64万
  • 项目类别:
Assembly and Activation of Enzyme-ssDNA Complexes
酶-ssDNA复合物的组装和激活
  • 批准号:
    8018659
  • 财政年份:
    1993
  • 资助金额:
    $ 19.64万
  • 项目类别:
ASSEMBLY AND ACTIVATION OF ENZYME-SSDNA COMPLEXES
酶-SSDNA 复合物的组装和激活
  • 批准号:
    2691547
  • 财政年份:
    1993
  • 资助金额:
    $ 19.64万
  • 项目类别:
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