Phase separation as an emerging regulatory framework in antibody class switching and genome stability

The spatial and temporal organization of nuclear processes is increasingly interpreted through principles associated with liquid-liquid phase separation (LLPS), whereby multivalent interactions among proteins and nucleic acids generate dynamic, membraneless assemblies. In DNA repair, such assemblies have been proposed to coordinate damage sensing, signaling, and repair pathway choice; however, their causal contribution in physiological immune contexts remains under active investigation. Antibody class switch recombination (CSR) provides a stringent immunological model in which to examine these concepts, as activated B lymphocytes must efficiently rejoin programmed DNA double-strand breaks (DSBs) across long genomic distances while suppressing aberrant chromosomal rearrangements. Emerging evidence indicates that CSR involves dynamic RNA-protein assemblies enriched for 53BP1, heterogeneous nuclear ribonucleoproteins such as HNRNPU, and transcription-associated RNA scaffolds, with properties consistent with biomolecular condensation. These assemblies are proposed to function as a CSR-specific regulatory hub-or "switchosome"-that concentrates non-homologous end joining factors, enforces repair pathway choice, and integrates transcription, RNA structure, and chromatin architecture at immunoglobulin heavy-chain (IgH) switch regions. Rather than treating LLPS as universally established, this review critically evaluates experimental evidence supporting condensate-like behavior in CSR-associated repair compartments, distinguishing demonstrated mechanisms from LLPS-consistent or speculative models. We further discuss how disruption of condensate dynamics-either through impaired assembly or pathological stabilization-can compromise repair fidelity, contributing to immunodeficiency and B cell lymphomagenesis. By positioning CSR as a paradigm for studying higher-order nuclear organization during programmed genome rearrangements, this review highlights how condensate-based regulation may contribute to immune diversification and genome stability.