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

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.
项目总结

项目成果

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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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