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NORAD诱导的Pumilio相分离是基因组稳定所需的
2021-06-13 14:32

美国德州大学西南医学中心Joshua T. Mendell小组发现,NORAD诱导的Pumilio相分离是基因组稳定所需的。2021年6月9日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示,液-液相分离是亚细胞区室化的主要机制。尽管将RNA分离成相分离的缩合物广泛地影响RNA代谢,但特定RNA是否以及如何使用相分离来调节相互作用因子,如RNA结合蛋白(RBP),以及这种调节相互作用的表型后果仍了解很少。

研究人员发现,RNA驱动的相分离是长链非编码RNA(lncRNA)控制RBP活性并维持哺乳动物细胞基因组稳定性的关键机制。lncRNA NORAD通过抑制 Pumilio(PUM)蛋白来防止异常有丝分裂。结果表明,NORAD可以通过使相分离的PUM浓缩物(称为NP体)形成,在竞争中胜过数以千计的其他PUM结合转录物来抑制PUM。PUM募集的双重机制(涉及多价PUM-NORAD和PUM-PUM相互作用)使得NORAD能够在NP体内竞争性地隔离超化学计量的PUM。NORAD驱动的PUM相分离中断会导致PUM过度活跃和基因组不稳定,而合成RNA会导致PUM浓缩物的形成,从而挽救这种不稳定。

这些结果揭示了一种机制:RNA驱动的相分离可以调节RBP活性并确定该过程在基因组维护中的重要作用。NORAD和其他lncRNA的重复序列结构表明,相分离可能是一种广泛使用的lncRNA介导的调控机制。

附:英文原文

Title: NORAD-induced Pumilio phase separation is required for genome stability

Author: Mahmoud M. Elguindy, Joshua T. Mendell

Issue&Volume: 2021-06-09

Abstract: Liquid–liquid phase separation is a major mechanism of subcellular compartmentalization1,2. Although the segregation of RNA into phase-separated condensates broadly affects RNA metabolism3,4, whether and how specific RNAs use phase separation to regulate interacting factors such as RNA-binding proteins (RBPs), and the phenotypic consequences of such regulatory interactions, are poorly understood. Here we show that RNA-driven phase separation is a key mechanism through which a long noncoding RNA (lncRNA) controls the activity of RBPs and maintains genomic stability in mammalian cells. The lncRNA NORAD prevents aberrant mitosis by inhibiting Pumilio (PUM) proteins5,6,7,8. We show that NORAD can out-compete thousands of other PUM-binding transcripts to inhibit PUM by nucleating the formation of phase-separated PUM condensates, termed NP bodies. Dual mechanisms of PUM recruitment, involving multivalent PUM–NORAD and PUM–PUM interactions, enable NORAD to competitively sequester a super-stoichiometric amount of PUM in NP bodies. Disruption of NORAD-driven PUM phase separation leads to PUM hyperactivity and genome instability that is rescued by synthetic RNAs that induce the formation of PUM condensates. These results reveal a mechanism by which RNA-driven phase separation can regulate RBP activity and identify an essential role for this process in genome maintenance. The repetitive sequence architecture of NORAD and other lncRNAs9,10,11 suggests that phase separation may be a widely used mechanism of lncRNA-mediated regulation.

DOI: 10.1038/s41586-021-03633-w

Source: https://www.nature.com/articles/s41586-021-03633-w

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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