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Review
. 2022 Oct 28;50(19):10817-10838.
doi: 10.1093/nar/gkac866.

A sePARate phase? Poly(ADP-ribose) versus RNA in the organization of biomolecular condensates

Elizaveta E Alemasova  1 , Olga I Lavrik  1   2
Affiliations
Review

A sePARate phase? Poly(ADP-ribose) versus RNA in the organization of biomolecular condensates

Elizaveta E Alemasova et al. Nucleic Acids Res. .

Abstract

Condensates are biomolecular assemblies that concentrate biomolecules without the help of membranes. They are morphologically highly versatile and may emerge via distinct mechanisms. Nucleic acids-DNA, RNA and poly(ADP-ribose) (PAR) play special roles in the process of condensate organization. These polymeric scaffolds provide multiple specific and nonspecific interactions during nucleation and 'development' of macromolecular assemblages. In this review, we focus on condensates formed with PAR. We discuss to what extent the literature supports the phase separation origin of these structures. Special attention is paid to similarities and differences between PAR and RNA in the process of dynamic restructuring of condensates during their functioning.

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Figures

Figure 1.
Figure 1.
A mechanism for the formation of nucleic-acid-based condensates. (A) Monolayer FUS recruitment on DNA (57). (B) FUS interaction with PAR and formation of compartments, concentrating PAR, FUS and damaged DNA (5,6,59).
Figure 2.
Figure 2.
A trans-acting catalyst-like mechanism for PAR-triggered FUS condensation.
Figure 3.
Figure 3.
RNA in biomolecular condensates. (A) A model for the formation of nuclear RNA foci in repeat expansion disorders. Increased RNA valency due to expansion of nucleotide repeat results in RNA gelation and sequestration of RNA molecules into nuclear foci (68). (B) RNA and LLPS in the creation of cellular polar systems. Top: one-cell stage C. elegans embryo. Competition of MEX-5 and PGL-3 proteins for mRNA binding regulates the formation of PGL-3 droplets (81). (C) LLPS-based channeling of ribosomal RNA (rRNA) flux out of the nucleolus. It is proposed that relatively nascent rRNA are available for multiple interactions with scaffolding proteins of the GC-matrix, while rRNA binding with ribosomal proteins decreases their valency, thus disturbing nucleolar LLPS and resulting in the effective emission of fully assembled pre-ribosomal particles (82). (D) Re-entrant liquid condensation. Top: a schematic illustration of three different RNP (ribonucleoprotein complexes):RNA regimes. Bottom: a corresponding phase diagram. The arrow represents the passage of the system from ‘+’ to ‘–’-charged RNPs through a charge-neutral stage and charge inversion when the RNA concentration is increased (RNP concentration is fixed). The shaded area corresponds to the LLPS regime (II). During the condensate dissolution stage, the RNA flux into RNP droplets generates vacuolated coacervates (83).
Figure 4.
Figure 4.
PAR synthesis and cellular localization. (A) PARPs is performs the PARylation reaction in the form of 1. Intramolecular (in cis-) auto-modification, 2. Intermolecular (in trans-) auto-modification within PARP dimers and 3. trans-modification of non-PARP targets. The points of active PAR production—PAR ‘stars’—are detected by electron microscopy (95,96) or atomic force microscopy (97). (B) PAR is found in cells at several locations: 1.transcription factories; 2. DNA repair foci; 3. the nucleolus; 4. Cajal bodies; 5. telomeres; 6. ASK3 condensates; 7. in the form of protein-free PAR chains; 8. stress granules; 9. pathological aggregates; 10. the spindle; and in extracellular space as 11. a product of PARP2 located on T-cell surface; 12. free PAR chains released in the extracellular matrix due to cell necrosis.
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