Biomolecular condensates as arbiters of biochemical reactions inside the nucleus

Abstract

Liquid-liquid phase separation (LLPS) has emerged as a central player in the assembly of membraneless compartments termed biomolecular condensates. These compartments are dynamic structures that can condense or dissolve under specific conditions to regulate molecular functions. Such properties allow biomolecular condensates to rapidly respond to changing endogenous or environmental conditions. Here, we review emerging roles for LLPS within the nuclear space, with a specific emphasis on genome organization, expression and repair. Our review highlights the emerging notion that biomolecular condensates regulate the sequential engagement of molecules in multistep biological processes.

Fig. 1. LLPS in heterochromatin and genome organization.

a HP1 proteins associate with H3K9Me3 marks (red), oligomerize, and mediate the LLPS of heterochromatin. b Factors controlling the LLPS of nucleosome arrays. Biomolecular condensates formed by chromatin are modulated by several factors. Addition of the linker histone H1 (blue) and MeCP2 (red) proteins results in the formation of distinct and immiscible condensates. Acetylation of histone tails leads to the dissolution of the condensate, resulting in a more dispersed arrangement of the nucleosomes. Chromatin condensates can be reassembled upon the addition of bromodomain-containing proteins (green).

Fig. 2. LLPS in transcriptional regulation.

Biomolecular condensates composed of transcription factors and coactivators at super-enhancers and promoter sequences recruit RNA Pol II. Phosphorylation of RNA Pol II mediates its transition from the initiation condensate to the elongation condensate, which is composed of transcriptional elongation and splicing factors.

Fig. 3. LLPS in the compartmentalization of damaged DNA.

a Mammalian PARP-1 is an early responder at DNA damage sites and synthetizes long negatively charged PAR chains that interact with positively charged RGG motifs present on FUS proteins. LLPS of FUS allows the compartmentalization of the DNA damage site and the exclusion of specific factors, such as 53BP1. Upon PARG activation and FUS phosphorylation, the FUS condensate disassembles and allows for the enrichment and subsequent LLPS of 53BP1. This phenomenon is mediated, at least in part, by the oligomerization domain of 53BP1. The enrichment of the mediator component MED1 and RNA Pol II in either compartment remains to be determined. b Budding yeast Rad52 forms biomolecular condensates at sites of DNA damage. The condensates can concentrate tubulin and drive the polymerization of microtubule filaments. The filaments help mobilize damaged DNA inside of the nucleus to promote repair.