Molecular recognition by ADAR1 of Z-RNA within transcriptomes
ADAR1 对转录组中 Z-RNA 的分子识别
基本信息
- 批准号:10712207
- 负责人:
- 金额:$ 30.26万
- 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:2023-09-26 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenosineAdoptedAdoptionAffectAlu ElementsAutoimmuneAutoimmune DiseasesBase SequenceBindingBinding SitesBiological ProcessBiophysicsBrain DiseasesCellsContractsCytoplasmCytosineDNA Transposable ElementsDiseaseEnzymesEventGene Expression RegulationGeographyGoalsGuanosineHumanImmune responseImmune systemInfectionInfectious AgentInnate Immune ResponseInosineInterferonsJointsKnowledgeLeadLeftMalignant NeoplasmsMediatingMethodsMolecular ConformationNamesNuclearPlayPoint MutationPopulationPrevalenceProcessProtein IsoformsProteinsPublishingRNARNA ConformationRNA EditingRNA Recognition MotifRNA VirusesRegulationRoleSamplingSiteSpecificityStructureTechniquesWorkZ-Form DNAdsRNA adenosine deaminasein vivomolecular recognitionmutantnervous system disordernext generation sequencingplasma protein Zpseudotoxoplasmosis syndromeresponserestraintthree dimensional structuretranscriptometranscriptome sequencingtumortumor progression
项目摘要
Project Summary
RNA editing of cellular RNAs helps the cell distinguish between self and non-self RNAs. This
editing of adenosines into inosines is generally catalyzed by the `adenosine deaminase acting on
RNA-1' protein (ADAR1). A>I editing is augmented in tumors and upon infection, primarily
through the interferon-induced longer isoform of ADAR1 that comprises a Z-DNA/Z-RNA binding
domain named ‘Zα’ at its N-terminus. Misediting is implicated in neurological diseases such as
Aicardi-Goutières syndrome. Z-RNA in the form of repeats of cytosine and guanosine (CpG) in a
left-handed double-helical conformation has been proposed in cells, but the prevalence of such
structures and their exact role are unknown. In addition, many —if not most— regions proposed
to adopt a Z conformation do not resemble regular (CpG)n. How these local Z-RNA conformations
are generated within A-form helices, stabilized and regulated by Zα of ADAR1, as well as their
exact role in the function of these RNAs, remain unknown. Our hypothesis is that the binding
of Zα to Z-RNA plays an essential role during the editing process. Here, we propose to
answer the following questions: What is the mechanism for Z-RNA formation at CpG but also
non-CpG sequences? How widespread are transitions to Z-RNA across transcriptomes? Is Z-
RNA sampled in the free form or only adopted upon binding by Zα? What are the structural
features of Z-RNA recognition by Zα at non CpG sequences? We will first dynamically
characterize the propensity of various sequence contexts to adopt Z-RNA conformations.
This aim will use advanced NMR methods to characterize the sequence of events that lead an
RNA region from A-form to Z-form. Second, we will determine the unbiased 3D structure of
RNA fragments bound to Zα in solution. Finally, we will identify and localize Zα binding
sites and Zα-dependent A>I editing events. This aim will take advantage of the robust
expertise and support for next-generation sequencing on our campus and at a contracted
company. Overall, our joint work as co-PIs will provide a structural rationale for the formation of
Z-RNA and the resulting formation of A-Z junctions across a variety of RNAs. We ultimately aim
to explain how the Z-RNA binding domain of ADAR1 increases the specificity and activity of
ADAR1. Our findings will help beyond this application with proposing a comprehensive
mechanism for ADAR1 editing and its RNA-mediated transcriptome-wide regulation, and
contribute to understanding disease such as cancer or auto-immune deficiencies.
项目摘要
对细胞RNA的RNA编辑有助于细胞区分自体和非自体RNA。这
腺苷编辑成肌苷通常是由作用于肌苷的腺苷脱氨酶催化的
RNA-1‘蛋白(ADAR1)。A>;I编辑在肿瘤和感染时增强,主要是
通过干扰素诱导的包含Z-DNA/Z-RNA结合的更长的ADAR1亚型
在其N端命名为‘Zα’的域。编辑错误与神经系统疾病有关,如
艾卡迪-古蒂埃综合征。以胞嘧啶和鸟苷(CpG)重复形式存在的Z-RNA
在细胞中已经提出了左旋双螺旋构象,但这种构象的流行
结构和它们的确切作用尚不清楚。此外,许多地区--如果不是大多数地区--提议
采用Z构象不像规则的(CpG)n。这些局部Z-RNA构象如何
在A型螺旋中产生,由ADAR1的Zα稳定和调节,以及它们的
这些RNA在功能中的确切作用尚不清楚。我们的假设是,
Z-α到Z-RNA的转换在编辑过程中起着至关重要的作用。在此,我们建议
回答以下问题:CpG中Z-RNA的形成机制是什么,而且
非CpG序列?向Z-RNA的转变在转录本中有多普遍?是Z-
是以自由形式采样,还是仅在Zα结合时采用?什么是结构上的
Zα在非CpG序列上识别Z-RNA的特征?我们首先要动态地
表征各种序列上下文采用Z-RNA构象的倾向。
这一目标将使用先进的核磁共振方法来表征导致
从A-型到Z-型的RNA区域。第二,我们将确定无偏3D结构
在溶液中与Z-α结合。最后,我们将标识并本地化Zα绑定
站点和Zα依赖的A&>I编辑事件。这一目标将利用稳健的
在我们的园区和签约的
公司。总体而言,我们作为共同投资促进机构的联合工作将为形成
Z-RNA和由此形成的跨越各种RNA的A-Z连接。我们最终的目标是
为了解释ADAR1的Z-RNA结合域如何增加ADAR1的特异性和活性
ADAR1.我们的发现将有助于超越这一申请,提出一种全面的
ADAR1编辑机制及其RNA介导的转录组调控,以及
有助于了解癌症或自身免疫缺陷等疾病。
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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Quentin Vicens其他文献
Quentin Vicens的其他文献
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{{ truncateString('Quentin Vicens', 18)}}的其他基金
Structural determinants of viral RNAs resistant to exoribonucleases in the alphavirus supergroup
甲病毒超群中抗核糖核酸外切酶的病毒RNA的结构决定因素
- 批准号:
10311545 - 财政年份:2020
- 资助金额:
$ 30.26万 - 项目类别:
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