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NORAD-induced Pumilio phase separation is required for genome stability
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Journal Article
NORAD-induced Pumilio phase separation is required for genome stability
2021
Overview
Liquid–liquid phase separation is a major mechanism of subcellular compartmentalization
1
,
2
. Although the segregation of RNA into phase-separated condensates broadly affects RNA metabolism
3
,
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) proteins
5
–
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 lncRNAs
9
–
11
suggests that phase separation may be a widely used mechanism of lncRNA-mediated regulation.
The noncoding RNA
NORAD
maintains genome stability in mammalian cells by sequestering Pumilio proteins in phase-separated compartments.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 14/1
/ 14/19
/ 14/32
/ 38
/ 38/91
/ 45
/ 45/41
/ 82/83
/ Binding
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Mitosis
/ Proteins
/ RNA
/ RNA, Long Noncoding - chemistry
/ RNA, Long Noncoding - genetics
/ RNA, Long Noncoding - metabolism
/ RNA-Binding Proteins - chemistry
/ RNA-Binding Proteins - metabolism
/ Science
