Structural and Mechanistic basis for RNA Silencing
Structural and Mechanistic basis for RNA Silencing
批准号:
10623935
负责人:
IAN JOHN MACRAE
金额:
$68.1万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
未结题
起止时间:
2018-08-01 至 2028-07-31
关键词:
AddressAnimalsAreaBiochemicalBiological ProcessBiologyBrainCellsComplexCullin ProteinsDNA Transposable ElementsDevelopmentDouble-Stranded RNAFertilityGene ExpressionGene Expression RegulationGene SilencingGenesGenomeHealthHepatitis C virusHumanIntegral Membrane ProteinKnowledgeLiverMammalsMembrane Transport ProteinsMessenger RNAMicroRNAsMolecular GeneticsProcessProductionRNARNA InterferenceRNA TransportRNA VirusesResearchSmall Interfering RNASmall RNAStructural BiochemistryStructureTranscriptional Silencer ElementsTranslationsUbiquitinationViralViral GenomeVirus DiseasesWorkcancer preventionhuman diseaseinsightpiRNAprotein complexstructural biologytherapeutic RNAubiquitin-protein ligaseviral RNA
中文摘要
项目概要/摘要
RNA沉默是一个笼统的术语,用于描述一组不同的生物过程,其中小RNA,包括
PIWI相互作用RNA(piRNA)、microRNA(miRNAs)和小干扰RNA(siRNAs)沉默
基因.这项提案旨在利用我的团队在结构生物学和生物化学方面的专业知识,
解决阻碍当前对RNA理解的突出问题
生物学沉默。具体地说:1)piRNA,对于保护基因组免受转座所必需的
已经使用分子遗传学广泛地研究了piRNA相关的转录因子(TE),但是如何与piRNA相关的转录因子(TE)结合,
在动物中观察到的多种因素共同作用以产生有效的TE沉默仍然不清楚。我们将
通过发现RNA蛋白质的结构和生物化学活性来填补这一知识空白
复合物对皮尔纳功能至关重要。2)miRNA是细胞基因表达的普遍调节因子,
哺乳动物,但miRNAs本身是如何调节的,直到最近才被发现。我们将推进
通过确定靶向泛素化和破坏miRNA的结构基础,
蛋白质复合物通过最近发现的Cullin-RING E3泛素连接酶。3)虽然
miRNA的典型功能是沉默靶向mRNA,某些RNA病毒已经进化出
重新利用细胞miRNAs来稳定病毒基因组并刺激病毒基因的机制,
生产miRNA复合物被重定向以实现这些非经典的功能的机制是:
功能了解不多。我们正在通过调查互动来解决这一知识差距
丙型肝炎病毒(HCV)和肝脏特异性miRNA miR-122之间的关系,重点是了解
调节HCV翻译以使HCV复制的miR-122-HCV RNA复合物的结构
核糖核酸4)RNA沉默领域最古老、最有趣的谜团之一是,在某些情况下,
沉默RNA容易在动物细胞之间传递。这一发现的25年后,RNA的机制
动物细胞内的转运仍不清楚。我们正在通过确定
SID-1识别和转运RNA结构基础,一种广泛保守的整合膜
将双链核糖核酸运送到动物细胞中的蛋白质。预计这些综合研究将
提出克服上述主要知识障碍所需的见解,
了解人类健康,生育能力,病毒感染和基于RNA的疗法的进步。
英文摘要
Project Summary/Abstract
RNA Silencing is a blanket term for a diverse group of biological processes in which small RNAs, including
PIWI-interacting RNAs (piRNAs), microRNAs (miRNAs), and small interfering RNAs (siRNAs) silence
genes. This proposal aims to leverage my group’s expertise in structural biology and biochemistry to
address outstanding questions that stand as roadblocks to advancing the current understanding of RNA
Silencing biology. Specifically: 1) piRNAs, essential for defending the genome against transposable
elements (TEs), have been studied extensively using molecular genetics, but how piRNA-associated
factors work together to produce the potent TE-silencing observed in animals remains unclear. We will
address this knowledge gap by discovering the structures and biochemical activities of RNA-protein
complexes central to piRNA function. 2) miRNAs are ubiquitous regulators of cellular gene expression in
mammals, but how miRNAs themselves are regulated has only recently come to light. We will advance
this emerging area by determining the structural basis for targeted ubiquitination and destruction of miRNA-
protein complexes by the recently discovered ZSWIM8 Cullin-RING E3 ubiquitin ligase. 3) Although the
canonical function of miRNAs is to silence targeted mRNAs, certain RNA viruses have evolved
mechanisms to repurpose cellular miRNAs to instead stabilize their viral genomes and stimulate viral
production. The mechanisms by which miRNA complexes are redirected to achieve these non-canonical
functions are poorly understood. We are addressing this knowledge gap by investigating interactions
between Hepatitis C Virus (HCV) and the liver-specific miRNA miR-122, with a focus on understanding the
structures of miR-122–HCV RNA complexes that modulate HCV translation to enable replication of HCV
RNA. 4) One of the oldest and most intriguing mysteries of the RNA Silencing field is that, in some cases,
silencing RNAs readily pass between animal cells. 25 years after this discovery, the mechanisms for RNA
transport into animal cells remain unclear. We are addressing this shortcoming by determining the
structural basis for RNA recognition and transport by SID-1, a broadly conserved integral membrane
protein that transports double-stranded RNA into animal cells. The combined studies are expected to
produce insights necessary to overcome the major knowledge barriers described above, with implications
for understanding human health, fertility, viral infection, and the advancement of RNA-based therapies.
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Assembly of the Bacterial Ribosome with Circularly Permuted rRNA.
用循环排列的 rRNA 组装细菌核糖体。
DOI:
10.1101/2024.04.10.588894
发表时间:
2024
期刊:
bioRxiv : the preprint server for biology
影响因子:
--
作者:
[Dong,Xiyu, Sheng,Kai, Gebert,LucaFR, Aiyer,Sriram, MacRae,IanJ, Lyumkis,Dmitry, Williamson,JamesR]
通讯作者:
Williamson,JamesR
DOI:
10.15252/embr.202255806
发表时间:
2023-06-05
期刊:
EMBO reports
影响因子:
7.7
作者:
[]
通讯作者:
DOI:
10.1073/pnas.2103671118
发表时间:
2021-08-17
期刊:
Proceedings of the National Academy of Sciences of the United States of America
影响因子:
11.1
作者:
[Chahal J, Gebert LFR, Camargo C, MacRae IJ, Sagan SM]
通讯作者:
Sagan SM
DOI:
10.1093/nar/gkac571
发表时间:
2022-09-23
期刊:
NUCLEIC ACIDS RESEARCH
影响因子:
14.9
作者:
[Xiao, Yao, MacRae, Ian J.]
通讯作者:
MacRae, Ian J.
Structural studies put phage defense mystery on the RADAR.
结构研究将噬菌体防御之谜置于雷达上。
DOI:
10.1016/j.cell.2023.02.003
发表时间:
2023
期刊:
Cell
影响因子:
64.5
作者:
[Wiryaman,Timothy, MacRae,IanJ]
通讯作者:
MacRae,IanJ
共 11 条
Mouse models for decoding microRNA regulation in diverse tissues and cell types
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批准号:10194631
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项目类别:
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资助金额:$22.19万
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财政年份:2021
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负责人:IAN JOHN MACRAE
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依托单位:
Mouse models for decoding microRNA regulation in diverse tissues and cell types
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批准号:10043075
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项目类别:
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资助金额:$26.63万
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财政年份:2020
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负责人:IAN JOHN MACRAE
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依托单位:
Structural and Mechanistic basis for RNA Silencing
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批准号:9979882
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项目类别:
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资助金额:$67.73万
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财政年份:2018
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负责人:IAN JOHN MACRAE
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依托单位:
Structural and Mechanistic basis for RNA Silencing
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批准号:10448453
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项目类别:
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资助金额:$67.73万
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财政年份:2018
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负责人:IAN JOHN MACRAE
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依托单位:
Structural and Mechanistic basis for RNA Silencing
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批准号:10213093
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项目类别:
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资助金额:$67.73万
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财政年份:2018
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负责人:IAN JOHN MACRAE
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依托单位:
Structure and Mechanism of the RISC-loading Complex
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批准号:9133428
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项目类别:
-
资助金额:$38.02万
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财政年份:2015
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负责人:IAN JOHN MACRAE
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依托单位:
Methods for controlling small RNA stability
-
批准号:9022315
-
项目类别:
-
资助金额:$25.12万
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财政年份:2015
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负责人:IAN JOHN MACRAE
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依托单位:
Structure and Mechanism of the RISC-loading Complex
-
批准号:9314277
-
项目类别:
-
资助金额:$38.02万
-
财政年份:2015
-
负责人:IAN JOHN MACRAE
-
依托单位:
Structural Basis for RNA Silencing by Human Argonaute2
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批准号:8708908
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项目类别:
-
资助金额:$36.01万
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财政年份:2013
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负责人:IAN JOHN MACRAE
-
依托单位:
Structural Basis for RNA Silencing by Human Argonaute2
-
批准号:8852646
-
项目类别:
-
资助金额:$36.01万
-
财政年份:2013
-
负责人:IAN JOHN MACRAE
-
依托单位:
Structural Basis for RNA Silencing by Human Argonaute2
-
批准号:8579676
-
项目类别:
-
资助金额:$36.01万
-
财政年份:2013
-
负责人:IAN JOHN MACRAE
-
依托单位:
3D STRUCTURE OF THE HUMAN RISC-LOADING COMPLEX
-
批准号:8362257
-
项目类别:
-
资助金额:$0.03万
-
财政年份:2011
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负责人:IAN JOHN MACRAE
-
依托单位:
STRUCTURAL STUDIES OF THE RNA INTERFERENCE MACHINERY
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批准号:8362459
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项目类别:
-
资助金额:$3.86万
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财政年份:2011
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负责人:IAN JOHN MACRAE
-
依托单位:
STRUCTURAL STUDIES OF THE RNA INTERFERENCE MACHINERY
-
批准号:8169680
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项目类别:
-
资助金额:$2.2万
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财政年份:2010
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负责人:IAN JOHN MACRAE
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依托单位:
3D STRUCTURE OF THE HUMAN RISC-LOADING COMPLEX
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批准号:8170240
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项目类别:
-
资助金额:$0.03万
-
财政年份:2010
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负责人:IAN JOHN MACRAE
-
依托单位:
Structure and Mechanism of the RISC-loading Complex
-
批准号:7931265
-
项目类别:
-
资助金额:$5.03万
-
财政年份:2009
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负责人:IAN JOHN MACRAE
-
依托单位:
STRUCTURAL STUDIES OF THE RNA INTERFERENCE MACHINERY
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批准号:7956452
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项目类别:
-
资助金额:$2.19万
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财政年份:2009
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负责人:IAN JOHN MACRAE
-
依托单位:
Structure and Mechanism of the RISC-loading Complex
-
批准号:7996046
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项目类别:
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资助金额:$34.34万
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财政年份:2008
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负责人:IAN JOHN MACRAE
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依托单位:
Structure and Mechanism of the RISC-loading Complex
-
批准号:8204417
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项目类别:
-
资助金额:$34.34万
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财政年份:2008
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负责人:IAN JOHN MACRAE
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依托单位:
STRUCTURAL STUDIES OF THE RNA INTERFERENCE MACHINERY
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批准号:7723585
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项目类别:
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资助金额:$1.26万
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财政年份:2008
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负责人:IAN JOHN MACRAE
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依托单位:
海外基金