G-Quadruplexes in Nuclear Biomolecular Condensates

Abstract

G-quadruplexes (G4s) have long been implicated in the regulation of chromatin packaging and gene expression. These processes require or are accelerated by the separation of related proteins into liquid condensates on DNA/RNA matrices. While cytoplasmic G4s are acknowledged scaffolds of potentially pathogenic condensates, the possible contribution of G4s to phase transitions in the nucleus has only recently come to light. In this review, we summarize the growing evidence for the G4-dependent assembly of biomolecular condensates at telomeres and transcription initiation sites, as well as nucleoli, speckles, and paraspeckles. The limitations of the underlying assays and the remaining open questions are outlined. We also discuss the molecular basis for the apparent permissive role of G4s in the in vitro condensate assembly based on the interactome data. To highlight the prospects and risks of G4-targeting therapies with respect to the phase transitions, we also touch upon the reported effects of G4-stabilizing small molecules on nuclear biomolecular condensates.

Keywords: G-quadruplex; chromatin structure; liquid–liquid phase separation; membraneless condensates.

Figure 1

Molecular grammar of the biomolecular condensates and presumed G4 contacts within the condensates. (a) Schematic representation of the condensate formation through the liquid–liquid phase separation (LLPS). (b) Typical constituents and their interactions. (c) Major types of transient LLPS-driving contacts. (d) Schematic representation of the G4 structures. (e) Typical examples of the transient contacts in the protein mixtures with ss/dsNA and G4 NA.

Figure 2

Effects of the G4s on the conformational transitions of the LLPS-driving proteins. (a) Nucleophosmin (NPM). The IDR- and ND-mediated binding of NPM to the G4 prevents intramolecular contacts within the NPM IDR, promotes intermolecular NPM–RM interactions, and thus facilitates the LLPS. (b) Heterochromatin protein 1α (HP1α). The HR-mediated binding of HP1α to the G4 prevents HP1α HR–CTE contacts, stabilizes the extended HP1α conformation, promotes intermolecular HP1α–H3Kme2/3 conformation, and thus facilitates the LLPS and heterochromatinization.

Figure 3

G4s in nuclear biomolecular condensates. (a) Schematic representation of typical nuclear condensates with G4-prone DNA/RNA. (b) Details on the nucleoli organization. (c) Details on the organization of sub-telomeric heterochromatin and shelterin. (d) Presumed organization of Pol II condensates upon active transcription.