Mechanisms of RPA, Recombinases, and Mediators in Homologous Recombination

同源重组中 RPA、重组酶和介体的机制

基本信息

  • 批准号:
    10238051
  • 负责人:
  • 金额:
    $ 30.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-10 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Homologous recombination (HR) is critical for the maintenance of genomic stability, and functions to eliminate DNA double-strand breaks and chromosomal lesions. Mutations in HR mediators dictate the pathological progression of many cancers and hereditary disorders. HR is initiated when a double-stranded DNA break is nucleolytically resected to generate single-stranded DNA (ssDNA) overhangs, which are readily coated and protected by Replication Protein A (RPA). The Breast Cancer Type 2 Susceptibility (BRCA2) protein functions to remove and remodel RPA and promote binding of the RAD51 recombinase, which then catalyzes strand exchange and drives recombination. Our long-term goals are to gain a mechanistic understanding of the temporal sequence of ssDNA handoff between these HR mediators and how these mediators compete for access to ssDNA and its overall contribution to diseases such as cancer. RPA is composed of multiple distinct DNA binding domains (DBDs) and binds with high affinity to ssDNA. The intrinsic DNA binding dynamics (binding, dissociation and remodeling) of individual DBDs are hypothesized to dictate when, where, and how RPA functions. For several decades the four DBDs of RPA have be classified as high affinity (DBDs-A & B) and low affinity (DBDs-C & D) based on experimental measurements of ssDNA binding affinity of isolated DBDs and have shaped models for RPA mechanism in DNA replication, repair and recombination. Using non-canonical amino acids, we developed a fluorescence-based method to capture the dynamics of individual DBDs in the context of the full-length protein. In contrary to classical models, we uncovered that the high-affinity DBDs are dynamic and are outcompeted by the trimerization core of RPA. In lieu of these exciting discoveries of RPA mechanism, we here propose to uncover how the BRCA2 mediator influences the dynamics of RPA-DBDs to promote the formation of the RAD51 filament during HR. We will establish how the context and type of DNA structures that are encountered in HR affect RPA-DBD dynamics [Aim 1]. We will investigate the importance of a regulatory hotspot in RPA that would modulate the interaction between RPA and the BRCA2-DSS1 complex [Aim 2]. Finally, using fluorescent versions of BRCA2, RAD51 and RAD52, we will establish the mechanism of ssDNA handoff from RPA to RAD51 during HR [Aim 3].
项目总结

项目成果

期刊论文数量(0)
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Edwin Antony其他文献

Edwin Antony的其他文献

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{{ truncateString('Edwin Antony', 18)}}的其他基金

Coordination of DNA Metabolism by Replication Protein A
复制蛋白 A 协调 DNA 代谢
  • 批准号:
    10623523
  • 财政年份:
    2023
  • 资助金额:
    $ 30.3万
  • 项目类别:
Mechanisms of RPA, Recombinases, and Mediators in Homologous Recombination
同源重组中 RPA、重组酶和介体的机制
  • 批准号:
    10589636
  • 财政年份:
    2022
  • 资助金额:
    $ 30.3万
  • 项目类别:
Mechanisms of RPA, Recombinases, and Mediators in Homologous Recombination
同源重组中 RPA、重组酶和介体的机制
  • 批准号:
    10576598
  • 财政年份:
    2022
  • 资助金额:
    $ 30.3万
  • 项目类别:
Acquisition of an Optima Analytical Ultracentrifuge
购买 Optima 分析超速离心机
  • 批准号:
    10177290
  • 财政年份:
    2021
  • 资助金额:
    $ 30.3万
  • 项目类别:
Mechanisms of DNA hand-off during lesion repair in BER and NER supplement
BER 和 NER 补充中损伤修复过程中 DNA 传递的机制
  • 批准号:
    9895224
  • 财政年份:
    2019
  • 资助金额:
    $ 30.3万
  • 项目类别:
Mechanisms of DNA hand-off during lesion repair in BER and NER
BER 和 NER 损伤修复过程中 DNA 传递的机制
  • 批准号:
    10377257
  • 财政年份:
    2019
  • 资助金额:
    $ 30.3万
  • 项目类别:
Mechanisms of RPA, Recombinases, and Mediators in Homologous Recombination
同源重组中 RPA、重组酶和介体的机制
  • 批准号:
    10810537
  • 财政年份:
    2019
  • 资助金额:
    $ 30.3万
  • 项目类别:
Mechanisms of DNA hand-off during lesion repair in BER and NER
BER 和 NER 损伤修复过程中 DNA 传递的机制
  • 批准号:
    10334423
  • 财政年份:
    2019
  • 资助金额:
    $ 30.3万
  • 项目类别:
Mechanisms of DNA hand-off during lesion repair in BER and NER
BER 和 NER 损伤修复过程中 DNA 传递的机制
  • 批准号:
    9981216
  • 财政年份:
    2019
  • 资助金额:
    $ 30.3万
  • 项目类别:
Mechanisms of RPA, Recombinases, and Mediators in Homologous Recombination
同源重组中 RPA、重组酶和介体的机制
  • 批准号:
    10015322
  • 财政年份:
    2019
  • 资助金额:
    $ 30.3万
  • 项目类别:

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