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NORAD-induced Pumilio phase separation is required for genome stability
Mahmoud M Elguindy1,2, Joshua T Mendell3,4,5,6
1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|June 10, 2021
Summary
Long noncoding RNA NORAD uses phase separation to inhibit Pumilio proteins, maintaining genomic stability. Disrupting this RNA-driven process causes genome instability, highlighting its crucial role in cell regulation.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Liquid-liquid phase separation drives subcellular organization.
- RNA metabolism is influenced by phase-separated RNA condensates.
- Mechanisms by which specific RNAs regulate RNA-binding proteins (RBPs) via phase separation are unclear.
Purpose of the Study:
- Investigate RNA-driven phase separation in regulating RBP activity.
- Determine the role of the long noncoding RNA (lncRNA) NORAD in controlling Pumilio (PUM) proteins.
- Elucidate the function of NORAD-mediated phase separation in maintaining genomic stability.
Main Methods:
- Studied NORAD's interaction with PUM proteins in mammalian cells.
- Investigated the formation of PUM condensates (NP bodies) nucleated by NORAD.
- Assessed the impact of disrupting NORAD-driven phase separation on PUM activity and genome stability.
- Utilized synthetic RNAs to rescue genome instability by inducing PUM condensates.
Main Results:
- NORAD competitively inhibits PUM proteins by nucleating phase-separated PUM condensates (NP bodies).
- Multivalent PUM-NORAD and PUM-PUM interactions allow NORAD to sequester large amounts of PUM.
- Disruption of NORAD-driven phase separation results in PUM hyperactivity and genome instability.
- Synthetic RNAs that induce PUM condensate formation rescue genome instability.
Conclusions:
- RNA-driven phase separation is a key mechanism for lncRNA-mediated RBP regulation.
- NORAD utilizes phase separation to control PUM activity and maintain genomic stability.
- Phase separation is a critical regulatory mechanism for lncRNAs, potentially widespread due to repetitive sequence elements.
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