SLX4 as a mediator of crossover pathway decisions in mammalian meiosis

SLX4 作为哺乳动物减数分裂中交叉途径决策的中介者

基本信息

  • 批准号:
    10540369
  • 负责人:
  • 金额:
    $ 38.07万
  • 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:
    2019-01-30 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

The induction of hundreds of double strand breaks (DSB) during prophase I of meiosis initiates homologous recombination (HR), which can result in the formation of crossovers (CO) that are essential for maintaining chromosome interactions through until, and ensuring accurate segregation at, the first meiotic division. Only 10% of DSBs are destined to become COs, the others being repaired as non-crossovers (NCO), but all DSBs must be repaired in a timely and robust fashion to prevent genome damage. Two distinct classes of COs can occur: a major class I machinery, involving components of the DNA mismatch repair (MMR) pathway, and a minor class II pathway, driven by the MUS81-EME1 endonuclease. The mechanisms by which selection of these CO pathways, or NCO pathways, occurs remain unclear, although the placement and frequency of the final CO tally must be stringently and exquisitely regulated to ensure accurate segregation at the first meiotic division. In mouse, the Fanconi Anemia (FA) related protein, SLX4, is important for directing CO events towards one of the two major pathways; mice lacking Slx4 exhibit a shift towards class I COs, loss of class II COs, and persistent unrepaired DSBs at the end of prophase I, phenotypes similar to that of mice lacking Mus81. This indicates that SLX4 may regulate class II CO events. SLX4 interacts with a large number of DNA repair factors, including several structure specific endonucleases (SSEs; XPF-ERCC1, MUS81-EME1, SLX1), as well as components of the FA and MMR pathways. In mouse, we have demonstrated that its interaction with SLX1 is not critical for DSB repair, but that it interacts with the meiosis-specific MMR heterodimer, MutSγ. Moreover, our studies indicate a functional interaction with BLM helicase, which regulates CO/NCO decisions in late prophase I through the dissolution of double Holliday Junction (dHJ) repair intermediates. We have also identified a novel interaction with another helicase in the FA pathway, FANCJ. The goal of the current proposal is to elucidate the role SLX4 in driving different DSB repair pathways during prophase I, and we hypothesize that this role depends on its interaction with key players in the repair network. In Aim 1, we will explore the genetic interactions between BLM, SLX4, and MUS81, specifically asking whether SLX4 is functioning to orchestrate class II events, or whether it is required to promote BLM-mediate dissolution of dHJs. In Aim 2, we will identify key functional interactions involving SLX4 during prophase I, using elegant mouse models to systematically interrogate each interacting partner of SLX4. In Aim 3, we will explore the roles and co-dependence of FANCJ and SLX4 in meiotic recombination during prophase I, using our mutant mouse models, combined with proteomics analysis, to understand how these two proteins interact functionally to regulate CO/NCO decisions in the context of the different DNA repair pathways with which they interact. Collectively, these studies represent the first functional analysis of the SLX4 interactome in mammalian meiosis, and will illuminate how genome-wide CO is achieved through intersecting repair pathways.
减数分裂前期数百条双链断裂(DSB)的诱导开始同源性

项目成果

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Paula Elaine Cohen其他文献

Paula Elaine Cohen的其他文献

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{{ truncateString('Paula Elaine Cohen', 18)}}的其他基金

Investigating the role of bromodomain-containing proteins in the production of viable spermatozoa and male fertility
研究含溴结构域蛋白在活精子产生和男性生育能力中的作用
  • 批准号:
    10157200
  • 财政年份:
    2021
  • 资助金额:
    $ 38.07万
  • 项目类别:
Spermatogenic gene regulation and infertility
生精基因调控与不育
  • 批准号:
    10157198
  • 财政年份:
    2021
  • 资助金额:
    $ 38.07万
  • 项目类别:
Spermatogenic gene regulation and infertility
生精基因调控与不育
  • 批准号:
    10398873
  • 财政年份:
    2021
  • 资助金额:
    $ 38.07万
  • 项目类别:
Investigating the role of bromodomain-containing proteins in the production of viable spermatozoa and male fertility
研究含溴结构域蛋白在活精子产生和男性生育能力中的作用
  • 批准号:
    10398876
  • 财政年份:
    2021
  • 资助金额:
    $ 38.07万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10398875
  • 财政年份:
    2021
  • 资助金额:
    $ 38.07万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10157199
  • 财政年份:
    2021
  • 资助金额:
    $ 38.07万
  • 项目类别:
Spermatogenic gene regulation and infertility
生精基因调控与不育
  • 批准号:
    10615691
  • 财政年份:
    2021
  • 资助金额:
    $ 38.07万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10615692
  • 财政年份:
    2021
  • 资助金额:
    $ 38.07万
  • 项目类别:
Investigating the role of bromodomain-containing proteins in the production of viable spermatozoa and male fertility
研究含溴结构域蛋白在活精子产生和男性生育能力中的作用
  • 批准号:
    10615696
  • 财政年份:
    2021
  • 资助金额:
    $ 38.07万
  • 项目类别:
2020 Meiosis Gordon Research Conference and Gordon Research Seminar
2020年减数分裂戈登研究大会暨戈登研究研讨会
  • 批准号:
    9980585
  • 财政年份:
    2020
  • 资助金额:
    $ 38.07万
  • 项目类别:

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以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
  • 批准号:
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    25330237
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