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
项目总结/文摘
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
-
项目类别:
-
资助金额:$22.19万
-
财政年份:2021
-
负责人:IAN JOHN MACRAE
-
依托单位:
Mouse models for decoding microRNA regulation in diverse tissues and cell types
-
批准号:10043075
-
项目类别:
-
资助金额:$26.63万
-
财政年份:2020
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负责人:IAN JOHN MACRAE
-
依托单位:
Structural and Mechanistic basis for RNA Silencing
-
批准号:9979882
-
项目类别:
-
资助金额:$67.73万
-
财政年份:2018
-
负责人:IAN JOHN MACRAE
-
依托单位:
Structural and Mechanistic basis for RNA Silencing
-
批准号:10448453
-
项目类别:
-
资助金额:$67.73万
-
财政年份:2018
-
负责人:IAN JOHN MACRAE
-
依托单位:
Structural and Mechanistic basis for RNA Silencing
-
批准号:10213093
-
项目类别:
-
资助金额:$67.73万
-
财政年份:2018
-
负责人:IAN JOHN MACRAE
-
依托单位:
Structure and Mechanism of the RISC-loading Complex
-
批准号:9133428
-
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:
Methods for controlling small RNA stability
-
批准号:9022315
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项目类别:
-
资助金额:$25.12万
-
财政年份:2015
-
负责人:IAN JOHN MACRAE
-
依托单位:
Structure and Mechanism of the RISC-loading Complex
-
批准号:9314277
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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
-
财政年份:2013
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负责人:IAN JOHN MACRAE
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依托单位:
Structural Basis for RNA Silencing by Human Argonaute2
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批准号:8852646
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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: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
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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
-
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: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
-
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
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财政年份:2010
-
负责人:IAN JOHN MACRAE
-
依托单位:
Structure and Mechanism of the RISC-loading Complex
-
批准号:7931265
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项目类别:
-
资助金额:$5.03万
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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
-
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
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批准号:7996046
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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:
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
-
财政年份:2008
-
负责人:IAN JOHN MACRAE
-
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:
-
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
-
依托单位:
海外基金