A Molecular Grammar Governing the Driving Forces for Phase Separation of Prion-like RNA Binding Proteins

Wang, Jie; Choi, Jeong‐Mo; Holehouse, Alex S.; Lee, Hyun O.; Zhang, Xiaojie; Jahnel, Marcus; Maharana, Shovamayee; Lemaitre, Regis; Pozniakovsky, Andrei; Drechsel, David; Poser, Ina; Pappu, Rohit V.; Alberti, Simon; Hyman, Anthony

doi:10.1016/j.cell.2018.06.006

Cited by 1,488 publications

(2,387 citation statements)

References 67 publications

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“…noticed that a pH shift from 7.4 to 5.5 rapidly induced FUS optoDroplet formation without light induction ( Fig EV2D) and that also 53BP1, but not MDC1, formed optoDroplets under acidic pH ( Fig EV2E). Recent work on the FET (FUS, EWSR1, TAF15) protein family identified multivalent interactions between tyrosines (Y) and arginines (R) to promote phase separation (Wang et al, 2018). Next, we generated a series of deletion mutants to identify the sequence elements driving 53BP1 phase separation.…”

Section: Of 17mentioning

confidence: 99%

Phase separation of 53 BP 1 determines liquid‐like behavior of DNA repair compartments

et al. 2019

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The DNA damage response (DDR) generates transient repair compartments to concentrate repair proteins and activate signaling factors. The physicochemical properties of these spatially confined compartments and their function remain poorly understood. Here, we establish, based on live cell microscopy and CRISPR/Cas9‐mediated endogenous protein tagging, that 53BP1‐marked repair compartments are dynamic, show droplet‐like behavior, and undergo frequent fusion and fission events. 53BP1 assembly, but not the upstream accumulation of γH2AX and MDC1, is highly sensitive to changes in osmotic pressure, temperature, salt concentration and to disruption of hydrophobic interactions. Phase separation of 53BP1 is substantiated by optoDroplet experiments, which further allowed dissection of the 53BP1 sequence elements that cooperate for light‐induced clustering. Moreover, we found the tumor suppressor protein p53 to be enriched within 53BP1 optoDroplets, and conditions that disrupt 53BP1 phase separation impair 53BP1‐dependent induction of p53 and diminish p53 target gene expression. We thus suggest that 53BP1 phase separation integrates localized DNA damage recognition and repair factor assembly with global p53‐dependent gene activation and cell fate decisions.

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Section: Of 17mentioning

confidence: 99%

Phase separation of 53 BP 1 determines liquid‐like behavior of DNA repair compartments

et al. 2019

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“…[24] Other types of interactions, such as π-π and electrostatics between charged residues, play important roles as well. [24] Other types of interactions, such as π-π and electrostatics between charged residues, play important roles as well.…”

Section: Protein-rich Dropletsmentioning

confidence: 99%

“…[12] In the context of the cell, these systems are driven away from equilibrium, e.g., by chemical reactions. [24] The liquid-to-solid transition of the centrosome forming protein SPD-5 may be mediated by coiled-coil domains to establish a force-resistant meshwork for microtubule-mediated chromosome segregation. Accordingly, mechanisms must exist that regulate the nucleation as well as the size and the mechanical properties.…”

Section: Protein-rich Dropletsmentioning

confidence: 99%

Directed Growth of Biomimetic Microcompartments

et al. 2019

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twilight zone), it is widely recognized that the formation of micro-and nanocompartments is an essential ingredient of all forms of life. This spatial constraint serves numerous purposes, including the segregation and protection from the environment (to allow for individuality and maintenance), the establishment of gradients (to enable and make use of outof-equilibrium conditions), and the role of 2D and 3D confinement for self-organization phenomena, all of which serve to overcome the overall "dilution problem." In order to fulfill another cornerstone of life-proliferation-compartments also need to change with time by fusion, growth, and division. In particular, the dynamic growth of compartments is an essential prerequisite for enabling selfreproduction as a fundamental life process, both in simplistic systems such as droplets or fatty acid-based vesicles, as well as for lipid vesicle compartments with membranes that resemble the biomembranes of today's cells. In this context, we argue that growth deserves more attention, not only because growth precedes division but also because of the difficulty to realize growth compared to division, especially in the case of lipid vesicles, where budding and division has been observed in response to various factors. This growth aspect has also been recognized in basic theoretical models of living systems such as Ganti's chemoton, [1,2] for which the increase of membrane area (referred to as membrane formation) was postulated to be one of three subsystems, characterizing living entities from a chemical viewpoint. The autopoietic theory was also centered on the membrane but focused on self-maintenance rather than on (self-)reproduction. [3,4] However, such a self-maintaining system could also enter a self-reproduction mode, manifested by growth, if homeostatic misbalance leads to excess membrane formation as shown in a thought experiment by Luisi. [3] In this progress report, we review the existing approaches for growth of compartments in the context of bottom-up synthetic biology and protobiology. We consider mainly micrometer-sized compartments due to their characteristic cellular dimensions; this feature also ensures that the area and curvature of the interface or the bounding membrane has less influence on the enclosed solution. Microcompartments of various origins and chemistries have been used as protocell models, and many studies have addressed growth and division simultaneously in an ambitious effort to mimic self-reproduction. Contemporary biological cells are sophisticated and highly compartmentalized. Compartmentalization is an essential principle of prebiotic life as well as a key feature in bottom-up synthetic biology research.In this review, the dynamic growth of compartments as an essential prerequisite for enabling self-reproduction as a fundamental life process is discussed. The micrometer-sized compartments are focused on due to their cellular dimensions. Two types of compartments are considered, membraneless droplets and membrane-bound microcompartments. Gr...

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“…In addition, proteins with IDRs often also harbor RNA‐recognition motifs (RRMs), and the same proteins are usually enriched in RNA‐containing BioMCs. Interestingly, RNA‐binding domains in IDR‐containing proteins have been shown to be crucially important for undergoing LLPS, as multivalent interactions among, for instance, tyrosine residues in IDRs and arginine residues in RRMs appear to primarily govern the process . Of note, while most studies addressed the role of particular phase‐separating proteins in both LLPS and BioMC formation, only very recently did RNA itself move into focus of phase transition research.…”

Section: Liquid–liquid Phase Separation Is Impacted and Regulated Bymentioning

confidence: 99%

RNAs, Phase Separation, and Membrane‐Less Organelles: Are Post‐Transcriptional Modifications Modulating Organelle Dynamics?

Drino¹,

Schaefer²

2018

BioEssays

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Membranous organelles allow sub‐compartmentalization of biological processes. However, additional subcellular structures create dynamic reaction spaces without the need for membranes. Such membrane‐less organelles (MLOs) are physiologically relevant and impact development, gene expression regulation, and cellular stress responses. The phenomenon resulting in the formation of MLOs is called liquid–liquid phase separation (LLPS), and is primarily governed by the interactions of multi‐domain proteins or proteins harboring intrinsically disordered regions as well as RNA‐binding domains. Although the presence of RNAs affects the formation and dissolution of MLOs, it remains unclear how the properties of RNAs exactly contribute to these effects. Here, the authors review this emerging field, and explore how particular RNA properties can affect LLPS and the behavior of MLOs. It is suggested that post‐transcriptional RNA modification systems could be contributors for dynamically modulating the assembly and dissolution of MLOs.

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A Molecular Grammar Governing the Driving Forces for Phase Separation of Prion-like RNA Binding Proteins

Cited by 1,488 publications

References 67 publications

Phase separation of 53 BP 1 determines liquid‐like behavior of DNA repair compartments

Phase separation of 53 BP 1 determines liquid‐like behavior of DNA repair compartments

Directed Growth of Biomimetic Microcompartments

RNAs, Phase Separation, and Membrane‐Less Organelles: Are Post‐Transcriptional Modifications Modulating Organelle Dynamics?

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