权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Quentin Vicens
金额：
$ 30.26万
依托单位：
UNIVERSITY OF HOUSTON
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：
https://reporter.nih.gov/project-details/10712207
关键词：
Address Adenosine Adopted Adoption Affect Alu Elements Autoimmune Autoimmune Diseases Base Sequence Binding Binding Sites Biological Process Biophysics Brain Diseases Cells Contracts Cytoplasm Cytosine DNA Transposable Elements Disease Enzymes Event Gene Expression Regulation Geography Goals Guanosine Human Immune response Immune system Infection Infectious Agent Innate Immune Response Inosine Interferons Joints Knowledge Lead Left Malignant Neoplasms Mediating Methods Molecular Conformation Names Nuclear Play Point Mutation Population Prevalence Process Protein Isoforms Proteins Publishing RNA RNA Conformation RNA Editing RNA Recognition Motif RNA Viruses Regulation Role Sampling Site Specificity Structure Techniques Work Z-Form DNA dsRNA adenosine deaminase in vivo molecular recognition mutant nervous system disorder next generation sequencing plasma protein Z pseudotoxoplasmosis syndrome response restraint three dimensional structure transcriptome transcriptome sequencing tumor tumor 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.

项目总结