G-Quadruplexes: Structural Diversity and Emerging Roles in Biomolecular Condensation

Among non-classical nucleic acid secondary structures, G-quadruplexes (G4s) play diverse roles in cellular functions and disease pathogenesis. However, the molecular mechanisms underlying the assembly of endogenous G4s into punctate condensates in cells remain unclear. Biomolecular condensates can arise from weak multivalent intermolecular interactions involving proteins and/or nucleic acids; this phenomenon is frequently linked to liquid-liquid phase separation. Recent research has provided compelling evidence for G4s driving biomolecular condensation. In this review, we first summarize the latest breakthroughs in the structural classification of G4s. In addition to frequently reported intramolecular G4s, intermolecular G4s have also been observed in cellular environments. Next, we discuss the regulatory role of G4s in condensation. Although G4s can independently form condensates, they primarily serve as structural platforms that facilitate condensate formation and regulate their phase transitions. Ultimately, this review reveals the multifaceted physiological and pathological functions of G4-driven condensates, including chromatin organization, assembly of stress granules and paraspeckles, abnormal transcriptional activation, telomere maintenance, neurodegenerative disease-associated protein aggregation, and viral inclusion body formation.