scholarly journals Emerging Roles of Liquid–Liquid Phase Separation in Cancer: From Protein Aggregation to Immune-Associated Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Jiahua Lu ◽  
Junjie Qian ◽  
Zhentian Xu ◽  
Shengyong Yin ◽  
Lin Zhou ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Genome Stability ◽  
Liquid Phase Separation ◽  
Cellular Stress Response ◽  
Regulation Of Transcription ◽  
Membrane Structures ◽  
New Paradigm ◽  
Nuclear Speckles ◽  
Liquid Liquid Phase Separation

Liquid–liquid Phase Separation (LLPS) of proteins and nucleic acids has emerged as a new paradigm in the study of cellular activities. It drives the formation of liquid-like condensates containing biomolecules in the absence of membrane structures in living cells. In addition, typical membrane-less condensates such as nuclear speckles, stress granules and cell signaling clusters play important roles in various cellular activities, including regulation of transcription, cellular stress response and signal transduction. Previous studies highlighted the biophysical and biochemical principles underlying the formation of these liquid condensates. The studies also showed how these principles determine the molecular properties, LLPS behavior, and composition of liquid condensates. While the basic rules driving LLPS are continuously being uncovered, their function in cellular activities is still unclear, especially within a pathological context. Therefore, the present review summarizes the recent progress made on the existing roles of LLPS in cancer, including cancer-related signaling pathways, transcription regulation and maintenance of genome stability. Additionally, the review briefly introduces the basic rules of LLPS, and cellular signaling that potentially plays a role in cancer, including pathways relevant to immune responses and autophagy.

scholarly journals Pericentromeric heterochromatin is hierarchically organized and spatially contacts H3K9me2 islands in euchromatin

2019 ◽  
Author(s):  
Yuh Chwen G. Lee ◽  
Yuki Ogiyama ◽  
Nuno M. C. Martins ◽  
Brian J. Beliveau ◽  
David Acevedo ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Genome Stability ◽  
Repetitive Sequences ◽  
Liquid Phase Separation ◽  
Hierarchical Organization ◽  
Pericentromeric Heterochromatin ◽  
Chromosome Dynamics ◽  
Technical Challenges ◽  
Liquid Liquid Phase Separation

AbstractMembraneless pericentromeric heterochromatin (PCH) domains play vital roles in chromosome dynamics and genome stability. However, our current understanding of 3D genome organization does not include PCH domains because of technical challenges associated with repetitive sequences enriched in PCH genomic regions. We investigated the 3D architecture of Drosophila melanogaster PCH domains and their spatial associations with euchromatic genome by developing a novel analysis method that incorporates genome-wide Hi-C reads originating from PCH DNA. Combined with cytogenetic analysis, we reveal a hierarchical organization of the PCH domains into distinct “territories.” Strikingly, H3K9me2/3-enriched regions embedded in the euchromatic genome show prevalent 3D interactions with the PCH domain. These spatial contacts require H3K9me2/3 enrichment, are likely mediated by liquid-liquid phase separation, and may influence organismal fitness. Our findings have important implications for how PCH architecture influences the function and evolution of both repetitive heterochromatin and the gene-rich euchromatin.Author summaryThe three dimensional (3D) organization of genomes in cell nuclei can influence a wide variety of genome functions. However, most of our understanding of this critical architecture has been limited to the gene-rich euchromatin, and largely ignores the gene-poor and repeat-rich pericentromeric heterochromatin, or PCH. PCH comprises large part of most eukaryotic genomes, forms 3D PCH domains in nuclei, and plays vital role in chromosome dynamics and genome stability. In this study, we developed a new method that overcomes the technical challenges imposed by the highly repetitive PCH DNA, and generated a comprehensive picture of its 3D organization. Combined with image analyses, we revealed a hierarchical organization of the PCH domains. Surprisingly, we showed that distant euchromatic regions enriched for repressive epigenetic marks also dynamically interact with the main PCH domains. These 3D interactions are mediated by liquid-liquid phase separation mechanisms, similar to how oil and vinegar separate in salad dressing, and can influence the fitness of individuals. Our discoveries have strong implications for how seemingly “junk” DNA could impact functions in the gene-rich euchromatin.

scholarly journals A role for liquid-liquid phase separation in ESCRT-mediated nuclear envelope reformation

2019 ◽  
Author(s):  
Alexander von Appen ◽  
Dollie LaJoie ◽  
Isabel E. Johnson ◽  
Mike Trnka ◽  
Sarah M. Pick ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Nuclear Envelope ◽  
Genome Stability ◽  
Transmembrane Protein ◽  
Low Complexity ◽  
Liquid Phase Separation ◽  
Endosomal Sorting ◽  
Spindle Disassembly ◽  
Liquid Liquid Phase Separation

At mitotic exit, microtubule arrays are dismantled in concert with the reformation of the nuclear envelope. We show how the inner nuclear membrane protein, LEM2, exploits liquid-liquid phase separation to direct microtubule remodeling and nuclear envelope sealing via the Endosomal Sorting Complexes Required for Transport (ESCRT) pathway. LEM2 tethers membrane to chromatin disks through direct binding between its LEM motif and the chromatin-associated barrier-to-autointegration factor (BAF). Concurrently, a low-complexity domain within LEM2 undergoes liquid-liquid phase separation to coat spindle microtubule bundles. Spatially restricted, LEM2’s winged helix (WH) domain activates the ESCRT-II/ESCRT-III hybrid protein, CHMP7. Together LEM2 and CHMP7 copolymerize around microtubule bundles to form a molecular “O-ring” that promotes nuclear compartmentalization and initiates downstream ESCRT factor recruitment. These results demonstrate how multivalent interactions of a transmembrane protein, including those that mediate phase separation, coordinate localized ESCRT polymerization, mitotic spindle disassembly, and membrane fusion. Defects in this pathway compromise spindle disassembly, nuclear integrity, and genome stability.

scholarly journals Therapeutics—how to treat phase separation-associated diseases

2020 ◽  
Vol 4 (3) ◽  
pp. 331-342 ◽  
Author(s):  
Richard John Wheeler
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Conceptual Framework ◽  
Protein Function ◽  
Enzyme Inhibitors ◽  
Liquid Phase Separation ◽  
Post Translational Modification ◽  
New Paradigm ◽  
Associated Proteins ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation has drawn attention as many neurodegeneration or cancer-associated proteins are able to form liquid membraneless compartments (condensates) by liquid–liquid phase separation. Furthermore, there is rapidly growing evidence that disease-associated mutation or post-translational modification of these proteins causes aberrant location, composition or physical properties of the condensates. It is ambiguous whether aberrant condensates are always causative in disease mechanisms, however they are likely promising potential targets for therapeutics. The conceptual framework of liquid–liquid phase separation provides opportunities for novel therapeutic approaches. This review summarises how the extensive recent advances in understanding control of nucleation, growth and composition of condensates by protein post-translational modification has revealed many possibilities for intervention by conventional small molecule enzyme inhibitors. This includes the first proof-of-concept examples. However, understanding membraneless organelle formation as a physical chemistry process also highlights possible physicochemical mechanisms of intervention. There is huge demand for innovation in drug development, especially for challenging diseases of old age including neurodegeneration and cancer. The conceptual framework of liquid–liquid phase separation provides a new paradigm for thinking about modulating protein function and is very different from enzyme lock-and-key or structured binding site concepts and presents new opportunities for innovation.

scholarly journals Liquid–Liquid Phase Separation: Undergraduate Labs on a New Paradigm for Intracellular Organization

2020 ◽  
Vol 1 (1) ◽  
pp. 5
Author(s):  
Caroline P. Riedstra ◽  
Ryan McGorty
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Aqueous System ◽  
Liquid Phase Separation ◽  
New Paradigm ◽  
Interdisciplinary Field ◽  
Quantitative Image ◽  
Membrane Bound ◽  
Biophysical Techniques ◽  
Liquid Liquid Phase Separation

Recent work has shown that the intracellular environment is organized not only through membrane-bound organelles but also through fluid droplets that emerge through liquid–liquid phase separation (LLPS). Intracellular LLPS has attracted recent attention because these fluid droplets, termed biomolecular condensates or membraneless organelles, seem to play important roles in cells' responses to stress, gene regulation, and pathologies. Our understanding of intracellular LLPS has advanced through many quantitative biophysical techniques. Here, we describe a set of undergraduate lab activities that highlight these biophysical techniques. We use various optical microscopy methods and quantitative image analysis to characterize the physical properties of a model aqueous system that exhibits liquid–liquid phase separation. These lab activities can form a multiweek module that exposes students to this exciting new and interdisciplinary field that investigates how phase transitions organize the cell interior.

scholarly journals Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

2021 ◽  
Vol 433 (2) ◽  
pp. 166731
Author(s):  
Yanxian Lin ◽  
Yann Fichou ◽  
Andrew P. Longhini ◽  
Luana C. Llanes ◽  
Pengyi Yin ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Hydrophobic Interaction ◽  
Liquid Phase Separation ◽  
Liquid Liquid Phase Separation

scholarly journals Amyloid Aggregation under the Lens of Liquid–Liquid Phase Separation

2020 ◽  
pp. 368-378
Author(s):  
Yanting Xing ◽  
Aparna Nandakumar ◽  
Aleksandr Kakinen ◽  
Yunxiang Sun ◽  
Thomas P. Davis ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Amyloid Aggregation ◽  
Liquid Liquid Phase Separation

scholarly journals Observation of liquid-liquid phase separation of ataxin-3 and quantitative evaluation of its concentration in a single droplet using Raman microscopy

2021 ◽  
Author(s):  
Kazuki Murakami ◽  
Shinji Kajimoto ◽  
Daiki Shibata ◽  
Kunisato Kuroi ◽  
Fumihiko Fujii ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Quantitative Evaluation ◽  
Raman Microscopy ◽  
Liquid Phase Separation ◽  
Biological Processes ◽  
Single Droplet ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...

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