A new study reports an unexpected function of the nucleolus as a protein quality control compartment for misfolded and aggregation-prone proteins. These findings have important implications for protein misfolding diseases.
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C9ORF72 poly-PR induces TDP-43 nuclear condensation via NEAT1 and is modulated by HSP70 activity.
Cell Rep
January 2025
Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan; Sustainable Chemical Science and Technology, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan; Department of Applied Chemistry, National Chiayi University, Chiayi City 600, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei 115, Taiwan. Electronic address:
The toxicity of C9ORF72-encoded polyproline-arginine (poly-PR) dipeptide is associated with its ability to disrupt the liquid-liquid phase separation of intrinsically disordered proteins participating in the formation of membraneless organelles, such as the nucleolus and paraspeckles. Amyotrophic lateral sclerosis (ALS)-related TAR DNA-binding protein 43 (TDP-43) also undergoes phase separation to form nuclear condensates (NCs) in response to stress. However, whether poly-PR alters the nuclear condensation of TDP-43 in ALS remains unclear.
View Article and Find Full Text PDFBioinformatic Analysis of Actin-Binding Proteins in the Nucleolus During Heat Shock.
Genes (Basel)
December 2024
Faculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047, Japan.
Background/objectives: Actin plays a crucial role not only in the cytoplasm, but also in the nucleus, influencing various cellular behaviors, including cell migration and gene expression. Recent studies reveal that nuclear actin dynamics is altered by cellular stresses, such as DNA damage; however, the effect of heat shock on nuclear actin dynamics, particularly in the nucleolus, remains unclear. This study aims to elucidate the contribution of nucleolar actin to cellular responses under heat shock conditions.
View Article and Find Full Text PDFDDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells.
Nat Commun
December 2024
Department of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical Center, New York, NY, USA.
Pluripotent stem cells possess a unique nuclear architecture characterized by a larger nucleus and more open chromatin, which underpins their ability to self-renew and differentiate. Here, we show that the nucleolus-specific RNA helicase DDX18 is essential for maintaining the pluripotency of human embryonic stem cells. Using techniques such as Hi-C, DNA/RNA-FISH, and biomolecular condensate analysis, we demonstrate that DDX18 regulates nucleolus phase separation and nuclear organization by interacting with NPM1 in the granular nucleolar component, driven by specific nucleolar RNAs.
View Article and Find Full Text PDFFunctions of the native NPM1 protein and its leukemic mutant.
Leukemia
December 2024
Institute of Hematology and Center for Hemato-Oncological research (CREO), University of Perugia and Santa Maria della Misericordia Hospital, Perugia, Italy.
The nucleophosmin (NPM1) gene encodes for the most abundant nucleolar protein. Thanks to its property to act as histone chaperone and to shuttle between the nucleus and cytoplasm, the NPM1 protein is involved in multiple cellular function that are here extensively reviewed and include the formation of the nucleolus through liquid-liquid phase separation, regulation of ribosome biogenesis and transport, control of DNA repair and centrosome duplication as well as response to nucleolar stress. NPM1 is mutated in about 30-35% of adult acute myeloid leukemia (AML).
View Article and Find Full Text PDFThe perinucleolar compartment and the oncogenic super-enhancers are part of the same phase-separated structure filled with phosphatidylinositol 4,5bisphosphate and long noncoding RNA HANR.
Adv Biol Regul
November 2024
Department of Biology of the Cell Nucleus, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic. Electronic address:
Article Synopsis
- Liquid-liquid phase separation in the cell nucleus plays a key role in gene regulation, chromatin organization, and DNA repair processes.
- The study utilized lipid-interacting RNA sequencing (LIPRNAseq) and confocal microscopy to explore the interaction of phosphatidylinositol 4,5 bisphosphate (PIP2) with specific RNA, identifying a PIP2-binding RNA motif and its colocalization with long non-coding RNA HANR in the perinucleolar compartment.
- The findings suggest a link between PIP2, lncHANR, and oncogenic super-enhancers, indicating their potential as prognostic markers for cancer and highlighting the importance of understanding lipid metabolism and RNA interactions for future cancer treatment strategies.
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