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

Jiahua Lu,Junjie Qian,Zhentian Xu,Shengyong Yin,Wu Zhang,Shusen Zheng,Lin Zhou

doi:10.3389/fcell.2021.631486

Abstract

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.

Highlights

Intracellular components are compartmentalized, respectively, in living cells to facilitate the regulation of cellular activities in time and space
All the aberrations in each step collectively result in the occurrence and progression of cancer
Thermodynamic forces derived from various cellular activities, such as RNA transcription, posttranslational modification (PTM), and m6A modification, cooperatively regulate phase separation

Summary

INTRODUCTION

Intracellular components are compartmentalized, respectively, in living cells to facilitate the regulation of cellular activities in time and space. It was later shown that they were engaged without an enclosing membrane (Yanagawa et al, 1995; Schwarz-Romond et al, 2005; Kim W. et al, 2013) These membrane-less organelles or structures exhibit significant liquid-like characteristics and are typically formed through a physicochemical process called liquid–liquid phase separation (LLPS) (Brangwynne et al, 2009). RBPs, such as RNA recognition motifs, were reported to play a role in RNA stability and metabolism These proteins were shown to be responsible for interactions with RNAs during LLPS, which leads to the formation of nuclear RNP bodies, P-bodies, and stress granules (Clery et al, 2008). This is considered as an RNA-induced lowering of saturation concentration for LLPS, which is a prevalent effect on proteins (Lin et al, 2015; Molliex et al, 2015; Saha et al, 2016)

REGULATION OF LLPS IN CELLULAR ACTIVITIES

THE EMERGING ROLE OF LLPS IN CANCER

Maintenance of Genome Stability

Findings

CONCLUSION