当前位置: X-MOL 学术Nature › 论文详情
NORAD-induced Pumilio phase separation is required for genome stability
Nature ( IF 42.778 ) Pub Date : 2021-06-09 , DOI: 10.1038/s41586-021-03633-w
Mahmoud M. Elguindy, Joshua T. Mendell

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.



中文翻译:

NORAD 诱导的 Pumilio 相分离是基因组稳定性所必需的

液-液相分离是亚细胞区室化1,2的主要机制。虽然将 RNA 分离成相分离的凝聚物广泛影响 RNA 代谢3,4,但特定 RNA 是否以及如何使用相分离来调节相互作用因素,如 RNA 结合蛋白 (RBP),以及这种调节相互作用的表型后果,是不太了解。在这里,我们表明 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5,6,7,8 来防止异常有丝分裂。我们表明NORAD通过使相分离的 PUM 缩合物(称为 NP 体)的形成成核,可以在竞争中胜过数千种其他 PUM 结合转录物以抑制 PUM。PUM 募集的双重机制,涉及多价PUM- NORAD和 PUM-PUM 相互作用,使NORAD能够在 NP 体内竞争性地隔离超化学计量数量的 PUM。NORAD驱动的 PUM 相分离的中断会导致 PUM 过度活跃和基因组不稳定,而合成 RNA 会导致 PUM 缩合物的形成,从而挽​​救这种不稳定。这些结果揭示了一种机制,通过这种机制,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的重复序列结构和其他 lncRNA 9,10,11表明相分离可能是 lncRNA 介导的调节的广泛使用的机制。

更新日期:2021-06-09
全部期刊列表>>
virulence
欢迎新作者ACS
中国作者高影响力研究精选
虚拟特刊
屿渡论文,编辑服务
浙大
上海中医药大学
深圳大学
上海交通大学
南方科技大学
浙江大学
清华大学
徐晶
张大卫
彭孝军
北京大学
隐藏1h前已浏览文章
课题组网站
新版X-MOL期刊搜索和高级搜索功能介绍
ACS材料视界
华辉
天合科研
x-mol收录
试剂库存
down
wechat
bug