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KREH2 解旋酶通过对规范和“兼职”gRNA 利用的相反调节来抑制循环阶段布鲁氏锥虫 ND7 mRNA 编辑，从而形成一种提出的 mRNA 结构。

KREH2 helicase represses ND7 mRNA editing in procyclic-stage Trypanosoma brucei by opposite modulation of canonical and 'moonlighting' gRNA utilization creating a proposed mRNA structure.

机构信息

Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.

Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3FL, UK.

出版信息

Nucleic Acids Res. 2024 Oct 28;52(19):11940-11959. doi: 10.1093/nar/gkae699.

DOI:10.1093/nar/gkae699
PMID:39149912
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11514453/
Abstract

Unknown factors regulate mitochondrial U-insertion/deletion (U-indel) RNA editing in procyclic-form (PCF) and bloodstream-form (BSF) T. brucei. This editing, directed by anti-sense gRNAs, creates canonical protein-encoding mRNAs and may developmentally control respiration. Canonical editing by gRNAs that specify protein-encoding mRNA sequences occurs amid massive non-canonical editing of unclear sources and biological significance. We found PCF-specific repression at a major early checkpoint in mRNA ND7, involving helicase KREH2-dependent opposite modulation of canonical and non-canonical 'terminator' gRNA utilization. Terminator-programmed editing derails canonical editing and installs proposed repressive structure in 30% of the ND7 transcriptome. BSF-to-PCF differentiation in vitro recreated this negative control. Remarkably, KREH2-RNAi knockdown relieved repression and increased editing progression by reverting canonical/terminator gRNA utilization. ND7 transcripts lacking early terminator-directed editing in PCF exhibited similar negative editing control along the mRNA sequence, suggesting global modulation of gRNA utilization fidelity. The terminator is a 'moonlighting' gRNA also associated with mRNA COX3 canonical editing, so the gRNA transcriptome seems multifunctional. Thus, KREH2 is the first identified repressor in developmental editing control. This and our prior work support a model whereby KREH2 activates or represses editing in a stage and substrate-specific manner. KREH2's novel dual role tunes mitochondrial gene expression in either direction during development.

摘要

未知因素调节前鞭毛体（PCF）和血液体（BSF）阶段的 T. brucei 中线粒体 U-插入/缺失（U-indel）RNA 编辑。这种由反义 gRNA 指导的编辑产生了规范的蛋白编码 mRNA，并可能在发育上控制呼吸。由指定蛋白编码 mRNA 序列的 gRNA 进行的规范编辑发生在大量非规范编辑之中，这些编辑的来源和生物学意义尚不清楚。我们发现 PCF 中存在一种主要的早期 mRNA ND7 检查点特异性抑制，涉及解旋酶 KREH2 对规范和非规范“终止子”gRNA 利用的相反调节。终止子编程编辑使规范编辑脱轨，并在 ND7 转录组的 30%中安装拟议的抑制性结构。体外 BSF 到 PCF 的分化重新创建了这种负调控。值得注意的是，KREH2-RNAi 敲低通过逆转规范/终止子 gRNA 利用来缓解抑制并增加编辑进展。在 PCF 中缺乏早期终止子指导编辑的 ND7 转录本在 mRNA 序列上表现出类似的负编辑控制，这表明 gRNA 利用保真度的全局调节。终止子是一种“兼职”gRNA，也与 mRNA COX3 规范编辑相关，因此 gRNA 转录组似乎具有多功能性。因此，KREH2 是发育编辑控制中第一个被鉴定的抑制剂。这和我们之前的工作支持了一种模型，即 KREH2 以阶段和底物特异性的方式激活或抑制编辑。KREH2 的新的双重作用在发育过程中以任意方向调节线粒体基因表达。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/28fac19e1a51/gkae699fig10.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/c821a6031e83/gkae699fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/da3d8eb70634/gkae699fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/dfef69b6cfe7/gkae699fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/28fac19e1a51/gkae699fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/6f40651fa8d3/gkae699figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/b870679ede70/gkae699fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/2418df18b651/gkae699fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/3d6d8b9af33d/gkae699fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/8dc81b63aede/gkae699fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/e31280a88758/gkae699fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/876cf28bfc4e/gkae699fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/c821a6031e83/gkae699fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/da3d8eb70634/gkae699fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/dfef69b6cfe7/gkae699fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476f/11514453/28fac19e1a51/gkae699fig10.jpg

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