Emerging evidence suggests that liquid-liquid phase separation (LLPS) represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells (also known as biomolecular condensates or droplets). Recent studies have revealed evidences that indicate that LLPS plays a vital role in human health and diseases. In this review, we describe our current understanding of LLPS and summarize its physiological functions. We further describe the role of LLPS in the development of human diseases. Additionally, we review the recently developed methods for studying LLPS. Although LLPS research is in its infancy-but is fast-growing-it is clear that LLPS plays an essential role in the development of pathophysiological conditions. This highlights the need for an overview of the recent advances in the field to translate our current knowledge regarding LLPS into therapeutic discoveries.

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Liquid-liquid phase separation in human health and diseases.

In the past decade, membraneless assemblies known as biomolecular condensates have been reported to play key roles in many cellular functions by compartmentalizing specific proteins and nucleic acids in subcellular environments with distinct properties. Furthermore, growing evidence supports the view that biomolecular condensates often form by phase separation, in which a single-phase system demixes into a two-phase system consisting of a condensed phase and a dilute phase of particular biomolecules. Emerging understanding of condensate function in normal and aberrant cellular states, and of the mechanisms of condensate formation, is providing new insights into human disease and revealing novel therapeutic opportunities. In this Perspective, we propose that such insights could enable a previously unexplored drug discovery approach based on identifying condensate-modifying therapeutics (c-mods), and we discuss the strategies, techniques and challenges involved. 

/pdf/modulating-biomolecular-condensates-a-novel-approach-to-drug-ck96z134.pdf

Modulating biomolecular condensates: a novel approach to drug discovery

Signalling mechanisms and cellular functions of SUMO

Regulation of Promoter Proximal Pausing of RNA Polymerase II in Metazoans.

Spatial organization of cellular processes in membranous or membrane-less organelles (MLOs, alias molecular condensates) is a key concept for compartmentalizing biochemical pathways. Prime examples of MLOs are the nucleolus, PML nuclear bodies, nuclear splicing speckles or cytosolic stress granules. They all represent distinct sub-cellular structures typically enriched in intrinsically disordered proteins and/or RNA and are formed in a process driven by liquid-liquid phase separation. Several MLOs are critically involved in proteostasis and their formation, disassembly and composition are highly sensitive to proteotoxic insults. Changes in the dynamics of MLOs are a major driver of cell dysfunction and disease. There is growing evidence that post-translational modifications are critically involved in controlling the dynamics and composition of MLOs and recent evidence supports an important role of the ubiquitin-like SUMO system in regulating both the assembly and disassembly of these structures. Here we will review our current understanding of SUMO function in MLO dynamics under both normal and pathological conditions.

/pdf/sumo-glue-or-solvent-for-phase-separated-ribonucleoprotein-uabvmumir5.pdf

Anwit S. Pandit

Papers

Stress-induced nuclear condensation of NELF drives transcriptional downregulation.