Involvement of Noncanonical Short RNAs in gene repression through the RNA-induced-silencing complex

非规范短 RNA 通过 RNA 诱导沉默复合物参与基因抑制

基本信息

  • 批准号:
    10701797
  • 负责人:
  • 金额:
    $ 32.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-09 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

ABSTRACT MicroRNAs have been studied for over two decades and found to impact extensively on various cellular functions like differentiation, proliferation and oncogenesis through regulation of gene expression using the Argonaute (Ago) containing RNA-induced silencing complex (RISC). In the cell, however, microRNAs co-exist with a nearly equal abundance of non-canonical short RNAs (ncsRNAs) that were not believed to enter the RISC. This has begun to change with our discovery that some members of the ncsRNAs, the tRNA derived fragments (tRFs) enter into RISC and silence gene expression, and others do not. The 18-26 base long tRF-3a molecules are derived from tRNAs by processes very different from the biogenesis of microRNAs, and yet repress gene expression by incorporation into Ago-RISC (RISC). In Aim 1 we will focus on specific tRF sub-classes, tRF-3b and tRF-1, that do not enter into Ago-RISC, to identify the surveillance pathways that keep short RNAs from dysregulating gene expression through RISC. We will study a methyltransferase that inactivates tRF-3b molecules by modifications on the RNA, a modification that is also regulated by demethylases that are inactivated by Isocitrate Dehydrogenase (IDH) mutations, seen in many cancers. We will also focus on an RNAse that degrades tRF-1 molecules to prevent them from entering into RISC and silencing gene expression. The results will reveal how the surveillance mechanisms work and how pathogenic or therapeutic alteration of the surveillance mechanisms will alter gene expression and improve RNA mediated therapy. In Aim 2 we will turn to ncsRNAs, exemplified by three tRF-3a molecules, that enter into RISC, silence gene expression and alter phenotypes of cancers and cancer cell-lines. We will test whether even in these cell line the tRF-3a molecules regulate gene expression by hijacking microRNA specific mechanisms and thus alter cellular phenotypes. We will also determine whether the ncsRNAs help or hinder microRNAs from doing their function. The field of short RNA mediated post-transcriptional gene regulation will be altered fundamentally by the recognition that microRNAs work in a complex milieu of other short RNAs that compete with or assist microRNAs, and that the cell has evolved mechanisms to protect the integrity of microRNA-mediated gene regulation.
摘要 MicroRNA已经研究了二十多年,发现广泛影响各种 通过基因调控细胞功能,如分化、增殖和肿瘤发生 使用含有RNA诱导的沉默复合物(RISC)的Argonaute(Ago)表达。在 然而,在细胞中,microRNA与几乎等量非典型短链共存 RNA(ncsRNA)被认为不进入RISC。这一点已经开始改变, 发现一些成员的ncsRNA,tRNA衍生片段(tRFs)进入 RISC和沉默基因表达,而其他人则没有。18-26个碱基长的tRF-3a分子 是通过与microRNA的生物发生非常不同的过程从tRNA衍生而来的, 通过掺入Ago-RISC(RISC)抑制基因表达。在目标1中,我们将重点关注 特定的tRF子类tRF-3b和tRF-1,不进入Ago-RISC,以识别 监视途径,防止短RNA通过RISC失调基因表达。 我们将研究一种甲基转移酶,它通过修饰 RNA,一种也受异柠檬酸盐灭活的脱甲基酶调节的修饰 脱氢酶(IDH)突变,见于许多癌症。我们还将重点关注一种RNA酶, 降解tRF-1分子,阻止其进入RISC并沉默基因 表情结果将揭示监测机制如何工作以及致病性如何 或治疗性改变监视机制将改变基因表达, RNA介导的治疗。在目标2中,我们将转向ncsRNA,以三个tRF-3a为例 分子,进入RISC,沉默基因表达和改变癌症的表型, 癌细胞系。我们将测试即使在这些细胞系中,tRF-3a分子是否调节 通过劫持microRNA特异性机制表达基因, 表型我们还将确定ncsRNAs是否有助于或阻碍microRNAs从 做他们的功能。短RNA介导的转录后基因调控领域将是 从根本上改变了认识到microRNA的工作在一个复杂的环境中的其他短 与microRNA竞争或协助microRNA,并且细胞已经进化出机制, 保护microRNA介导的基因调控的完整性。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Depletion of the m1A writer TRMT6/TRMT61A reduces proliferation and resistance against cellular stress in bladder cancer.
  • DOI:
    10.3389/fonc.2023.1334112
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    4.7
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Anindya Dutta其他文献

Anindya Dutta的其他文献

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{{ truncateString('Anindya Dutta', 18)}}的其他基金

Studies on ORC and double strand DNA break repair
ORC与双链DNA断裂修复的研究
  • 批准号:
    10377840
  • 财政年份:
    2021
  • 资助金额:
    $ 32.91万
  • 项目类别:
Studies on ORC and double strand DNA break repair
ORC与双链DNA断裂修复的研究
  • 批准号:
    10555198
  • 财政年份:
    2021
  • 资助金额:
    $ 32.91万
  • 项目类别:
Studies on ORC and double strand DNA break repair
ORC与双链DNA断裂修复的研究
  • 批准号:
    10328884
  • 财政年份:
    2021
  • 资助金额:
    $ 32.91万
  • 项目类别:
Mechanism of action of an lncRNA for directing muscle differentiation
lncRNA指导肌肉分化的作用机制
  • 批准号:
    10396900
  • 财政年份:
    2016
  • 资助金额:
    $ 32.91万
  • 项目类别:
Mechanism of action of an lncRNA for directing muscle differentiation
lncRNA指导肌肉分化的作用机制
  • 批准号:
    9914219
  • 财政年份:
    2016
  • 资助金额:
    $ 32.91万
  • 项目类别:
Effect of anti-S phase agents on human chromosomes
抗S期药物对人类染色体的影响
  • 批准号:
    8436839
  • 财政年份:
    2013
  • 资助金额:
    $ 32.91万
  • 项目类别:
Effect of anti-S phase agents on human chromosomes
抗S期药物对人类染色体的影响
  • 批准号:
    8608500
  • 财政年份:
    2013
  • 资助金额:
    $ 32.91万
  • 项目类别:
Effect of anti-S phase agents on human chromosomes
抗S期药物对人类染色体的影响
  • 批准号:
    8997926
  • 财政年份:
    2013
  • 资助金额:
    $ 32.91万
  • 项目类别:
Androgen and MicroRNAs in Prostate Cancer
前列腺癌中的雄激素和 MicroRNA
  • 批准号:
    8038178
  • 财政年份:
    2011
  • 资助金额:
    $ 32.91万
  • 项目类别:
MicroRNAs in differentiation of muscle
MicroRNA在肌肉分化中的作用
  • 批准号:
    7883986
  • 财政年份:
    2009
  • 资助金额:
    $ 32.91万
  • 项目类别:

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