Checkpoints and Double Strand Breaks in S. Pombe Meiosis

粟酒裂殖酵母减数分裂中的检查点和双链断裂

基本信息

  • 批准号:
    8499352
  • 负责人:
  • 金额:
    $ 32.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-06-01 至 2015-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Faithful chromosome segregation is essential to the production of viable meiotic products. While the regulation of unperturbed meiotic chromosome segregation is well understood, it is less known what happens when cells attempt meiosis in the presence of unexpected DNA damage. This proposal investigates the response to DNA damage in meiosis, using a fission yeast model system. Fission yeast is a powerful system in the analysis of damage response in the cell cycle, sharing many regulatory genes with humans. Previous studies have shown that the checkpoint system that works in proliferating cells to block the cell cycle in response to DNA damage is not functional in meiosis. Conditions that cause replication fork collapse appear to be compatible with meiotic progression. There is a genetic link between meiotic progression and the response of proliferating cells to alkylation damage that suggest translation synthesis polymerases may play a role in meiosis. These observations suggest that the meiotic response to DNA damage is substantially reprogrammed during differentiation. This is a renewal of a current project that has been funded for 1 year from ARRA (stimulus) funding. The first aim addresses the question of how the damage checkpoint kinase, Chk1, is reprogrammed in meiosis so that it does not respond to damage during S phase. The second aim asks how meiotic cells accommodate collapsing replication forks, which would be lethal during proliferation. The third aim proposes a novel role for trans-lesion synthesis (TLS) polymerases in meiosis. This is based on two observations: first, that the DDK kinase which functions during S phase also regulation meiosis and TLS, and second, that a separation of function allele in the kinase specifically disrupts meiotic divisions and TLS. The long term goal is to understand how the regulation of the damage response during meiS phase is modified to enable later meiotic events. The objective is to use fission yeast to dissect the molecular mechanisms that differ in the response to replication stress and S-phase damage in meiotic cells. The rationale is that knowledge of mechanisms that promote genome stability in meiosis will allow identification of genetic and environmental risk factors that impact human miscarriages and birth defects. The central hypothesis is that conserved activities that normally function to protect the genome are co-opted in meiosis to allow programmed genetic damage. The expected outcomes of this project are the identification and characterization of new molecular pathways. These will include potentially novel factors, likely to be conserved in higher eukaryotes. The positive impact will be a fundamental advance in understanding of the response of differentiating cells to DNA damage and genome stability, and a better understanding of risk factors during meiosis.
描述(由申请人提供):忠实的染色体隔离对于生产可行的减数分裂产品至关重要。虽然对不受干扰的减数分裂染色体分离的调节尚未得到充分了解,但鲜为人知的是,当细胞在存在意外DNA损伤的情况下尝试减数分裂时会发生什么。该提案使用裂变酵母模型系统研究了减数分裂中DNA损伤的反应。裂变酵母是分析细胞周期损伤反应的强大系统,与人类共享许多调节基因。 先前的研究表明,在增殖细胞中起作用以阻止细胞周期对DNA损伤的细胞周期的检查点系统在减数分裂中不起作用。导致复制叉塌陷的条件似乎与减数分裂进程兼容。减数分裂进程与增殖细胞对烷基化损伤的反应之间存在遗传联系,这表明翻译合成聚合酶可能在减数分裂中起作用。这些观察结果表明,在分化过程中对DNA损伤的减数分裂反应进行了重新编程。这是对当前项目的续签,该项目已从ARRA(刺激)资金中资助了1年。 第一个目的解决了损伤检查点激酶CHK1如何在减数分裂中重新编程的问题,以使其在s期间对损害无反应。第二个目标询问减数分裂细胞如何适应崩溃的复制叉,这在增殖过程中将是致命的。第三个目标提出了跨性质合成(TLS)聚合酶在减数分裂中的新作用。这是基于两个观察结果:首先,在S相期间起作用的DDK激酶还调节减数分裂和TLS,其次,激酶中功能等位基因的分离特异性破坏了减数分裂分裂和TLS。 长期目标是了解如何修改MEI阶段损伤响应的调节以实现以后的减数分裂事件。目的是利用裂变酵母来剖析减数分裂细胞中对复制应激和S相损伤反应的分子机制。理由是,对减数分裂中促进基因组稳定性的机制的了解将允许识别影响人类流产和出生缺陷的遗传和环境风险因素。中心假设是通常在减数分裂中选择了通常起作用以保护基因组的保守活动,以允许编程的遗传损害。该项目的预期结果是新分子途径的识别和表征。这些将包括可能在较高的真核生物中保守的潜在新因素。积极的影响将是了解分化细胞对DNA损伤和基因组稳定性的反应的基本进步,以及对减数分裂过程中危险因素的更好理解。

项目成果

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SUSAN L FORSBURG其他文献

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{{ truncateString('SUSAN L FORSBURG', 18)}}的其他基金

Mechanisms linking replication stress to genome instability in fission yeast
裂殖酵母中复制应激与基因组不稳定性的联系机制
  • 批准号:
    10595031
  • 财政年份:
    2016
  • 资助金额:
    $ 32.44万
  • 项目类别:
Mechanisms linking replication stress to genome instability in fission yeast
裂殖酵母中复制应激与基因组不稳定性的联系机制
  • 批准号:
    9893001
  • 财政年份:
    2016
  • 资助金额:
    $ 32.44万
  • 项目类别:
Mechanisms linking replication stress to genome instability in fission yeast
裂殖酵母中复制应激与基因组不稳定性的联系机制
  • 批准号:
    10404012
  • 财政年份:
    2016
  • 资助金额:
    $ 32.44万
  • 项目类别:
CBI: Chemistry Biology Interface
CBI:化学生物学接口
  • 批准号:
    9485969
  • 财政年份:
    2016
  • 资助金额:
    $ 32.44万
  • 项目类别:
Mechanisms linking replication stress to genome instability in fission yeast
裂殖酵母中复制应激与基因组不稳定性的联系机制
  • 批准号:
    10205564
  • 财政年份:
    2016
  • 资助金额:
    $ 32.44万
  • 项目类别:
Structural instability and DNA rearrangements in the centromere
着丝粒的结构不稳定和 DNA 重排
  • 批准号:
    8720618
  • 财政年份:
    2014
  • 资助金额:
    $ 32.44万
  • 项目类别:
Structural instability and DNA rearrangements in the centromere
着丝粒的结构不稳定和 DNA 重排
  • 批准号:
    8840617
  • 财政年份:
    2014
  • 资助金额:
    $ 32.44万
  • 项目类别:
Checkpoints and Double Strand Breaks in S. Pombe Meiosis
粟酒裂殖酵母减数分裂中的检查点和双链断裂
  • 批准号:
    8269785
  • 财政年份:
    2009
  • 资助金额:
    $ 32.44万
  • 项目类别:
Checkpoints and double strand breaks in S. pombe meiosis
粟酒裂殖酵母减数分裂中的检查点和双链断裂
  • 批准号:
    7846742
  • 财政年份:
    2009
  • 资助金额:
    $ 32.44万
  • 项目类别:
Checkpoints and Double Strand Breaks in S. Pombe Meiosis
粟酒裂殖酵母减数分裂中的检查点和双链断裂
  • 批准号:
    8131567
  • 财政年份:
    2009
  • 资助金额:
    $ 32.44万
  • 项目类别:

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相似海外基金

Checkpoints and Double Strand Breaks in S. Pombe Meiosis
粟酒裂殖酵母减数分裂中的检查点和双链断裂
  • 批准号:
    8269785
  • 财政年份:
    2009
  • 资助金额:
    $ 32.44万
  • 项目类别:
Checkpoints and Double Strand Breaks in S. Pombe Meiosis
粟酒裂殖酵母减数分裂中的检查点和双链断裂
  • 批准号:
    8131567
  • 财政年份:
    2009
  • 资助金额:
    $ 32.44万
  • 项目类别:
Checkpoints and Double Strand Breaks in S. Pombe Meiosis
粟酒裂殖酵母减数分裂中的检查点和双链断裂
  • 批准号:
    8686876
  • 财政年份:
    2009
  • 资助金额:
    $ 32.44万
  • 项目类别:
Covalent Modification of DNA and Protein by Bioactivated Antitumor Acylfulvenes
生物活性抗肿瘤酰基富烯对 DNA 和蛋白质的共价修饰
  • 批准号:
    7259793
  • 财政年份:
    2007
  • 资助金额:
    $ 32.44万
  • 项目类别:
Covalent Modification of DNA and Protein by Bioactivated Antitumor Acylfulvenes
生物活性抗肿瘤酰基富烯对 DNA 和蛋白质的共价修饰
  • 批准号:
    7496683
  • 财政年份:
    2007
  • 资助金额:
    $ 32.44万
  • 项目类别:
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