Dicer DNA nickase activity and its role in anti-viral immunity in human cells

Dicer DNA 切口酶活性及其在人体细胞抗病毒免疫中的作用

基本信息

  • 批准号:
    10724622
  • 负责人:
  • 金额:
    $ 8.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-21 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Abstract Dicer is a multi-domain ribonuclease III (RNase III) enzyme that produces small interfering RNAs (siRNAs) and microRNAs (miRNAs) from dsRNA precursors. RNA silencing mediated by these small RNAs is an important defense system against viral infection. Loss of Dicer causes loss of anti-viral immunity. Previous study in C. elegans showed that cleavage of the C. elegans RNase Dicer by pro- apoptotic caspase-3 produces a stable C-terminal fragment of Dicer that now functions as a deoxyribonuclease (DNase) in the developmental apoptosis pathway. However, even more than a decade after this study, whether the RNase-to-DNase conversion of Dicer by specific proteolysis occurs in any other animals including human remains unknown. Whether Dicer DNase has any role in anti-viral immunity also remains unknown. When cells are infected by viruses despite their anti-viral system, many of them undergo programmed cell death (PCD or apoptosis), which helps to abort the production and release of progeny viruses from the cells. Growing evidence indicates that some proteins have both ‘day- jobs’ in healthy cells and ‘death-jobs’ in cells undergoing PCD. Thus, evolution may have linked day-jobs and death-jobs in the same molecule to ensure that cell death is appropriately linked to and regulated by multiple normal cellular processes. In this proposal, we hypothesize that human Dicer has day-jobs as an RNase in RNA silencing pathway and death-jobs as a DNase in PCD pathway. Specifically, we will test the hypothesis that cleavage of the human Dicer by pro-apoptotic caspase-3 produces a stable C-terminal fragment of Dicer (Dcr-C) that functions as a DNase (DNA nickase) in the PCD pathway in human cells. We will also test the hypothesis that the conversion of Dicer to Dcr-C and its DNA nickase activity are crucial for anti-viral immunity. Our exciting preliminary studies showed that Dcr-C exhibits DNA nickase activity in test tube and in cells, supporting our hypotheses. If successful, the proposed studies employing biochemical and cellular approaches will form foundations for future animal studies of Dicer RNase-to-DNase conversion in PCD and anti-viral immunity in mammals. Understanding the physiological roles and molecular mechanisms of Dcr- C DNA nickase will reveal new regulatory mechanisms in the PCD pathway and anti-viral system including a novel link between RNA silencing and PCD via Dicer, both of which are crucial for anti-viral defense.
摘要 Dicer是一种多结构域核糖核酸酶III(RNase III)酶,其产生小的干扰, 来自dsRNA前体的RNA(siRNA)和microRNA(miRNA)。RNA沉默 这些小RNA是抵抗病毒感染的重要防御系统。切粒机损失 导致抗病毒免疫力丧失。 以前的研究在C. elegans显示C.线虫RNase Dicer 凋亡的caspase-3产生一个稳定的Dicer的C末端片段,它现在作为一个 脱氧核糖核酸酶(DNase)在发育性细胞凋亡途径中的作用。但更多 在这项研究之后的十多年中,是否特异性的Dicer的RNase到DNase的转化 蛋白质水解在包括人类在内的任何其他动物中发生仍然未知。是否切丁 脱氧核糖核酸酶在抗病毒免疫中有什么作用还不清楚。 当细胞被病毒感染时,尽管它们有抗病毒系统,它们中的许多细胞仍会经历 程序性细胞死亡(PCD或凋亡),这有助于中止生产和释放 从细胞中分离出后代病毒。越来越多的证据表明,一些蛋白质既有“白天”, 健康细胞中的“工作”和经历PCD的细胞中的“死亡工作”。因此,进化可能已经 在同一个分子中将日常工作和死亡工作联系起来,以确保细胞死亡是适当的, 与多种正常细胞过程相联系并受其调节。 在这个提议中,我们假设人类Dicer在RNA沉默中作为RNA酶有日常工作 途径和死亡-工作作为一种DNA酶在PCD途径。具体来说,我们将测试假设 通过促凋亡caspase-3切割人Dicer产生稳定的C-末端 Dicer片段(Dcr-C),在PCD途径中作为DNA酶(DNA切口酶)发挥作用, 人体细胞我们还将检验Dicer转化为Dcr-C及其DNA的假设 切口酶活性对于抗病毒免疫至关重要。我们令人兴奋的初步研究表明, Dcr-C在试管和细胞中显示DNA切口酶活性,支持我们的假设。如果 如果成功,将形成采用生物化学和细胞方法的拟议研究。 为将来在PCD和抗病毒中Dicer RNase到DNase转化的动物研究奠定了基础 哺乳动物的免疫力了解Dcr的生理作用和分子机制- C-DNA切口酶将揭示PCD途径和抗病毒系统中新的调控机制 包括RNA沉默和PCD之间通过Dicer的新联系,这两者对于 抗病毒防御

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Ryuya Fukunaga其他文献

Ryuya Fukunaga的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Ryuya Fukunaga', 18)}}的其他基金

Investigating the molecular functions and mechanisms of RNA-binding proteins crucial for gametogenesis
研究对配子发生至关重要的 RNA 结合蛋白的分子功能和机制
  • 批准号:
    10406577
  • 财政年份:
    2022
  • 资助金额:
    $ 8.19万
  • 项目类别:
Investigating the molecular functions and mechanisms of RNA-binding proteins crucial for gametogenesis
研究对配子发生至关重要的 RNA 结合蛋白的分子功能和机制
  • 批准号:
    10630355
  • 财政年份:
    2022
  • 资助金额:
    $ 8.19万
  • 项目类别:
Mechanism to regulate the length of small silencing RNAs
调节小沉默RNA长度的机制
  • 批准号:
    9980435
  • 财政年份:
    2017
  • 资助金额:
    $ 8.19万
  • 项目类别:

相似海外基金

The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
  • 批准号:
    EP/Z000920/1
  • 财政年份:
    2025
  • 资助金额:
    $ 8.19万
  • 项目类别:
    Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
  • 批准号:
    FT230100276
  • 财政年份:
    2024
  • 资助金额:
    $ 8.19万
  • 项目类别:
    ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
  • 批准号:
    MR/X024261/1
  • 财政年份:
    2024
  • 资助金额:
    $ 8.19万
  • 项目类别:
    Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
  • 批准号:
    DE240100388
  • 财政年份:
    2024
  • 资助金额:
    $ 8.19万
  • 项目类别:
    Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
  • 批准号:
    2889694
  • 财政年份:
    2023
  • 资助金额:
    $ 8.19万
  • 项目类别:
    Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
  • 批准号:
    2842926
  • 财政年份:
    2023
  • 资助金额:
    $ 8.19万
  • 项目类别:
    Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
  • 批准号:
    NC/X001644/1
  • 财政年份:
    2023
  • 资助金额:
    $ 8.19万
  • 项目类别:
    Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
  • 批准号:
    2337595
  • 财政年份:
    2023
  • 资助金额:
    $ 8.19万
  • 项目类别:
    Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
  • 批准号:
    2232190
  • 财政年份:
    2023
  • 资助金额:
    $ 8.19万
  • 项目类别:
    Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
  • 批准号:
    23K17514
  • 财政年份:
    2023
  • 资助金额:
    $ 8.19万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了