Roles of RNA Polymerases IV and V in siRNA-mediated gene silencing
RNA 聚合酶 IV 和 V 在 siRNA 介导的基因沉默中的作用
基本信息
- 批准号:9239452
- 负责人:
- 金额:$ 31.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-05-01 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAberrant DNA MethylationAllelesBindingBinding ProteinsBiochemicalBiogenesisBiological AssayC-terminalCentromereChromatinChromosome SegregationComplexCoupledCytosineDNADNA MethylationDNA Modification MethylasesDNA Polymerase IDNA Polymerase IIDNA SequenceDNA Transposable ElementsDNA-Directed RNA PolymeraseDNMT3aDRD1 geneDependenceDevelopmentDouble-Stranded RNAElementsEnvironmentEnzymesEukaryotaEventFemaleFission YeastFragile X SyndromeGene SilencingGenerationsGenesGeneticGenetic TranscriptionGenomicsGoalsGuide RNAHDAC6 geneHereditary DiseaseHeterochromatinHistone H3HumanHuman DevelopmentHuman GeneticsIn VitroLengthLysineMalignant NeoplasmsMediatingMethylationModelingOrganismOrthologous GenePathologyPathway interactionsPlant RNAPlantsPrecursor RNAProcessProductionProteinsRNARNA Polymerase IRNA chemical synthesisRNA-Directed DNA PolymeraseRNA-Directed RNA PolymeraseRecombinant ProteinsRecombinantsRecruitment ActivityRetrotransposonRoleSS DNA BPSignal TransductionSiteSmall Interfering RNASystemTestingTranscriptTranscription ElongationTransfer RNATransgenesUntranslated RNAVirusX ChromosomeX Inactivationchromatin modificationcohesincondensindosageendonucleaseenzyme pathwayexperimental studyflygenetic informationhistone modificationhuman diseasein vivoinnovationinsightmalematernal imprintpaternal imprintpiRNApromoterprotein protein interactionsynthetic nucleic acidtranscription factortranslocasetransmission process
项目摘要
All eukaryotes use three essential DNA-dependent RNA polymerases to decode genetic information
stored in DNA, namely RNA Polymerases I, II and III. Remarkably, plants have two more RNA polymerases,
abbreviated as Pol IV and Pol V, that evolved from Pol II to specialize in the synthesis of RNAs that guide gene
silencing, an important process in all living organisms for controlling retrotransposons, viruses or genes
important for development. Pols IV and V are key to a complicated RNA-directed DNA methylation (RdDM)
pathway. The pathway is initiated by Pol IV, acting in partnership and physical association with a RNA-
dependent RNA polymerase, RDR2 to transcribe DNA into short double-stranded RNAs (dsRNAs). These
dsRNAs are then trimmed, from either end, by the DICER endonuclease, DCL3, yielding 24 nt short interfering
RNAs (siRNAs). The siRNAs, loaded into ARGONAUTE 4 (AGO4), guide the siRNA-AGO complexes to sites
of Pol V transcription, where they bind to Pol V transcripts as well as to the C-terminal domain of the Pol V
largest subunit. The DNA methyltransferase, DRM2 (the ortholog of human DNMT3) is recruited, methylating
cytosines within the Pol V-transcribed DNA. Resulting heterochromatin formation is refractive to transcription
by Pols I, II or III. However, Pols IV and V are not repressed in this chromatin environment. Instead, helper
proteins that recognize cytosine methylation or repressive histone modifications are thought to recruit Pols IV
and V, taking the place of transcription factors and dispensing with conventional promoter elements.
There is much that we do not understand about the RdDM process. What unwinds DNA for Pols IV and
V to gain access to template strands? How are Pol IV and RDR2 activities coupled for dsRNA synthesis?
Where do Pol V transcripts begin and end, and how many siRNA-AGO complexes can bind them ? What do
the presumed Pol IV and Pol V helper proteins actually do? By devising new biochemical assays combined
with genetic, genomic and structural studies, our goal is to answer these questions in mechanistic detail.
In eukaryotes as diverse as humans, flies, worms and fission yeast, noncoding RNAs guide chromatin
modifications important for centromere function, transposon silencing, X-chromosome inactivation or imprinting
of paternal or maternal alleles. Of special relevance to our studies is the piRNA pathway that directs the
silencing of transposons in the human germline, thereby serving the same purpose, and using the same DNA
methylation machinery, as the RdDM pathway of plants. Controlled DNA methylation is critical, such that
aberrant DNA methylation and chromatin modification is implicated in the pathology of Rett, ICF, Prader-Willi,
Beckwith-Wiedemann and Fragile X syndromes, and in most forms of cancer. By understanding the biogenesis
and targeting mechanisms of noncoding RNAs in DNA methylation and gene silencing, our studies will
contribute new understanding of fundamental processes important for human development and disease.
所有真核生物都使用三种必需的DNA依赖性RNA聚合酶来解码遗传信息
储存在DNA中,即RNA聚合酶I、II和III。值得注意的是,植物有两个以上的RNA聚合酶,
缩写为Pol IV和Pol V,从Pol II进化而来,专门合成引导基因的RNA,
沉默是所有生物体中控制反转录转座子、病毒或基因的重要过程
对发展很重要。Pols IV和V是复杂的RNA指导的DNA甲基化(RdDM)的关键
通路该途径由Pol IV启动,与RNA-
依赖性RNA聚合酶RDR 2将DNA转录成短的双链RNA(dsRNA)。这些
然后通过DICER内切核酸酶DCL 3从任一端修剪dsRNA,产生24 nt短干扰RNA。
RNA(siRNA)。加载到ARGONAUTE 4(AGO 4)中的siRNA将siRNA-AGO复合物引导到位点
它们与Pol V转录物以及Pol V转录物的C-末端结构域结合,
最大的亚单位DNA甲基转移酶,DRM 2(人DNMT 3的直系同源物)被募集,甲基化
PolV转录的DNA中的胞嘧啶。由此产生的异染色质的形成是折射转录
第一,第二,第三然而,Pol IV和V在这种染色质环境中不受抑制。相反,助手
识别胞嘧啶甲基化或抑制性组蛋白修饰的蛋白质被认为可以募集Pos IV
和V,取代转录因子,不需要常规的启动子元件。
我们对RdDM流程有很多不了解。是什么解开了Pols IV和
获得模板链?Pol IV和RDR 2活性如何偶联用于dsRNA合成?
Pol V转录本的开始和结束位置,有多少siRNA-AGO复合物可以结合它们?什么
推测的Pol IV和Pol V辅助蛋白真的有作用吗通过设计新的生化检测方法,
通过遗传学、基因组学和结构研究,我们的目标是从机理上详细回答这些问题。
在人类、苍蝇、蠕虫和分裂酵母等多种真核生物中,非编码RNA引导染色质
对着丝粒功能、转座子沉默、X染色体失活或印记重要的修饰
父亲或母亲的等位基因。与我们的研究特别相关的是指导蛋白质合成的皮尔纳途径。
沉默人类生殖系中的转座子,从而达到相同的目的,并使用相同的DNA
甲基化机制,如植物的RdDM途径。受控的DNA甲基化是至关重要的,
异常的DNA甲基化和染色质修饰与Rett,ICF,Prader-Willi,
Beckwith-Wiedemann和脆性X综合征,以及大多数形式的癌症。通过了解生物起源
以及非编码RNA在DNA甲基化和基因沉默中的靶向机制,
有助于对人类发展和疾病的重要基本过程有新的认识。
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)
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CRAIG Stuart PIKAARD其他文献
CRAIG Stuart PIKAARD的其他文献
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{{ truncateString('CRAIG Stuart PIKAARD', 18)}}的其他基金
SPECIFICITY OF HISTONE ACETYLTRANSFERASE ENZYMES FROM ARABIDOPSIS THALIANA
拟南芥组蛋白乙酰转移酶的特异性
- 批准号:
7953917 - 财政年份:2009
- 资助金额:
$ 31.08万 - 项目类别:
SPECIFICITY OF HISTONE ACETYLTRANSFERASE ENZYMES FROM ARABIDOPSIS THALIANA
拟南芥组蛋白乙酰转移酶的特异性
- 批准号:
7721482 - 财政年份:2008
- 资助金额:
$ 31.08万 - 项目类别:
Roles of RNA Polymerases IV and V in siRNA-mediated gene silencing
RNA 聚合酶 IV 和 V 在 siRNA 介导的基因沉默中的作用
- 批准号:
8391724 - 财政年份:2006
- 资助金额:
$ 31.08万 - 项目类别:
Role of RNA polymerase IV in the heterochromatic siRNA pathway
RNA聚合酶IV在异染色质siRNA途径中的作用
- 批准号:
7599659 - 财政年份:2006
- 资助金额:
$ 31.08万 - 项目类别:
Roles of RNA Polymerases IV and V in siRNA-mediated gene silencing
RNA 聚合酶 IV 和 V 在 siRNA 介导的基因沉默中的作用
- 批准号:
8204558 - 财政年份:2006
- 资助金额:
$ 31.08万 - 项目类别:
Role of RNA polymerase IV in the heterochromatic siRNA pathway
RNA聚合酶IV在异染色质siRNA途径中的作用
- 批准号:
8037901 - 财政年份:2006
- 资助金额:
$ 31.08万 - 项目类别:
SPECIFICITY OF HISTONE ACETYLTRANSFERASE ENZYMES FROM ARABIDOPSIS THALIANA
拟南芥组蛋白乙酰转移酶的特异性
- 批准号:
7355309 - 财政年份:2006
- 资助金额:
$ 31.08万 - 项目类别:
Role of RNA polymerase IV in the heterochromatic siRNA pathway
RNA聚合酶IV在异染色质siRNA途径中的作用
- 批准号:
7088118 - 财政年份:2006
- 资助金额:
$ 31.08万 - 项目类别:
Role of RNA polymerase IV in the heterochromatic siRNA pathway
RNA聚合酶IV在异染色质siRNA途径中的作用
- 批准号:
7220652 - 财政年份:2006
- 资助金额:
$ 31.08万 - 项目类别:
Roles of RNA Polymerases IV and V in siRNA-mediated gene silencing
RNA 聚合酶 IV 和 V 在 siRNA 介导的基因沉默中的作用
- 批准号:
8041251 - 财政年份:2006
- 资助金额:
$ 31.08万 - 项目类别:
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