Noncoding RNAs are indispensable architects and regulators of biomolecular condensates

TL;DR

Noncoding RNAs play essential roles in forming and regulating membraneless organelles through liquid-liquid phase separation, impacting both normal and disease processes.

Contribution

This review highlights the diverse roles of noncoding RNAs as active modulators in biomolecular condensates, beyond their traditional protein-centric understanding.

Findings

Noncoding RNAs act as scaffolds, regulators, or clients in LLPS droplets.

They influence both physiological and pathological phase separation processes.

Emerging therapeutic strategies target ncRNA-driven condensates.

Abstract

Liquid-liquid phase separation (LLPS) is a biophysical mechanism by which certain biomolecules demix from the cytosol or nucleoplasm to form membraneless organelles. These droplet-like assemblies are dynamic and reversible, allowing selective enrichment of specific proteins and nucleic acids while excluding others. Classical examples include the nucleolus, P-bodies, and stress granules, all of which exhibit liquid-like behaviors such as rapid fusion, fission, and molecular exchange. Most importantly, the LLPS property has been implicated with a plethora of physiological and pathological processes. Historically, research on LLPS focused on protein drivers, especially RNA-binding proteins (RBPs) with low complexity domains or intrinsically disordered regions, contributing to multivalent weak interactions. However, it is now clear that RNA molecules especially noncoding RNAs are integral components and often active modulators of these condensates. Noncoding RNAs, including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), PIWI-interacting RNAs (piRNAs), and others, can serve as scaffolds, regulators, or clients within the LLPS droplets, thereby influencing both normal cellular organization and disease processes. This review provides an overview of current research on how ncRNAs contribute to LLPS across different cellular localizations and contexts, covering physiological condensates, disease linked phase separation, underlying molecular mechanisms, and emerging therapeutic implications.

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