Mechanisms of Genomic Stability by Mammalian Argonaute Proteins

哺乳动物 Argonaute 蛋白的基因组稳定性机制

基本信息

  • 批准号:
    10646245
  • 负责人:
  • 金额:
    $ 32.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Genome instability increases the rates of mutations, chromosomal rearrangements, and aneuploidy and drives many age-related human diseases, including cancer. The challenges of replicating our genome and epigenome with each cell division requires molecular pathways that ensure the propagation of stable genomes to daughter cells. To date, the roles of mammalian noncoding RNAs (ncRNAs) in the maintenance of genome stability is incompletely understood. We propose that filling this gap is essential to expand our knowledge of human development and homeostasis and to identify novel risk factors that contribute to human disease. In fission yeast, the RNA interference (RNAi) pathway acts during DNA synthesis at the repeats of pericentromeres via locally produced ncRNAs to establish the heterochromatin needed for genome stability. It is unclear if similar cell cycle-specific RNAi mechanisms of genome stability are present in mammals. In preliminary studies, we used mouse stem cell systems to map high-confidence interactions of the RNAi effector Argonaute (Ago) proteins with ncRNAs. We determined that Ago binds directly to pericentromeric ncRNAs. Furthermore, we found that pericentromeric ncRNAs are overexpressed during DNA synthesis in Ago-deficient cells and observed multiple signatures of genomic instability caused by full Ago depletion. In parallel, previous studies in mouse models have established that overexpression of pericentromeric ncRNA suffices to cause genomic instability and tumorigenesis. Based on these intriguing findings, we hypothesize that pericentromeric ncRNA expression, established via cell cycle-specific Ago regulation, is critical for the maintenance of genomic stability in mammalian cells, analogous to fission yeast. In this RO1 research project, we examine the potential roles of RNAi in preventing genomic instability caused by accumulating pericentromeric ncRNA and/or disruption of local heterochromatin structure. We propose to define cell cycle- specific Ago activities to elucidate the molecular triggers for pericentromere regulation and to determine how pericentromeric ncRNAs contribute to genome stability. In Aim 1, we will determine how and when Ago functions at pericentromeres for the establishment of heterochromatin. In Aim 2, we determine the direct molecular consequence of Ago recruitment to chromatin. Finally, in Aim 3, we will elucidate how ncRNAs control Ago activity at pericentromeres during cell cycle progression. These innovative studies will answer the long-standing question of whether the mammalian RNAi pathway contributes to the maintenance of pericentromere heterochromatin and genome stability and will break new ground in our understanding of RNA- mediated gene regulation. We predict these studies will drive and yield a framework for future strategies to modulate pericentromeric ncRNA in disease settings.
项目摘要/摘要 基因组不稳定会增加突变、染色体重排和非整倍体的比率,并导致 许多与年龄有关的人类疾病,包括癌症。复制我们的基因组和 每一次细胞分裂的表观基因组都需要分子途径来确保稳定基因组的繁殖 传给子代细胞。到目前为止,哺乳动物非编码RNA(NcRNAs)在基因组维持中的作用 人们对稳定性的理解并不完全。我们认为,填补这一空白对于扩大我们对 人类发展和动态平衡,并找出导致人类疾病的新的风险因素。在……里面 在裂解酵母中,RNA干扰(RNAi)途径在DNA合成过程中作用于 通过本地生产的ncRNA来建立基因组稳定所需的异染色质。它 目前尚不清楚哺乳动物中是否存在类似的细胞周期特异性RNAi基因组稳定机制。在……里面 初步研究,我们使用小鼠干细胞系统来绘制RNAi的高置信度相互作用图 与ncRNAs结合的效应蛋白。我们确定AGO直接与着丝粒周围结合 NcRNAs。此外,我们发现,在dna合成过程中,着丝粒周围的ncRNAs过表达。 并观察到由完整的AGO耗尽引起的基因组不稳定的多个特征。在……里面 类似的,先前在小鼠模型中的研究已经证实,着丝粒周围ncRNA的过度表达 足以导致基因组不稳定和肿瘤发生。基于这些有趣的发现,我们假设 通过细胞周期特异的AGO调节建立的着丝粒周围ncRNA的表达对于 在哺乳动物细胞中维持基因组稳定性,类似于分裂酵母。在这个RO1研究项目中, 我们研究了RNAi在防止由于积累而导致的基因组不稳定方面的潜在作用 着丝粒周围的ncRNA和/或局部异染色质结构的破坏。我们建议定义细胞周期-- 特异的AGO活性,以阐明着丝粒周围调控的分子触发因素,并确定如何 着丝粒周围的ncRNAs有助于基因组的稳定。在目标1中,我们将确定时间和方式 在着丝粒周围建立异染色质的功能。在目标2中,我们确定直接 AgO重新聚集到染色质的分子后果。最后,在目标3中,我们将阐明ncRNAs如何 控制细胞周期进程中着丝粒周围的AGO活性。这些创新的研究将回答 哺乳动物的RNAi途径是否有助于维持 着丝粒异染色质和基因组稳定性,将在我们对RNA的理解上开辟新的天地。 介导的基因调控。我们预测,这些研究将推动并为未来的战略提供一个框架 在疾病环境中调节着丝粒周围的ncRNA。

项目成果

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JESSE R ZAMUDIO其他文献

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{{ truncateString('JESSE R ZAMUDIO', 18)}}的其他基金

Mechanisms of Genomic Stability by Mammalian Argonaute Proteins
哺乳动物 Argonaute 蛋白的基因组稳定性机制
  • 批准号:
    10280983
  • 财政年份:
    2021
  • 资助金额:
    $ 32.76万
  • 项目类别:
Mechanisms of Genomic Stability by Mammalian Argonaute Proteins
哺乳动物 Argonaute 蛋白的基因组稳定性机制
  • 批准号:
    10471922
  • 财政年份:
    2021
  • 资助金额:
    $ 32.76万
  • 项目类别:
In vivo characterization of microRNA regulation
microRNA 调控的体内表征
  • 批准号:
    7915227
  • 财政年份:
    2009
  • 资助金额:
    $ 32.76万
  • 项目类别:
In vivo characterization of microRNA regulation
microRNA 调控的体内表征
  • 批准号:
    7676513
  • 财政年份:
    2009
  • 资助金额:
    $ 32.76万
  • 项目类别:
In vivo characterization of microRNA regulation
microRNA 调控的体内表征
  • 批准号:
    8127615
  • 财政年份:
    2009
  • 资助金额:
    $ 32.76万
  • 项目类别:

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