The Multifunctional SMC5/6 Complex in Genome Stability, Antiviral Restriction, and Human Disease.

The Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex is a key regulator of genome stability that participates in the recognition, stabilization, and processing of DNA intermediates generated during DNA replication and homologous recombination. Recent advances in structural and biochemical studies have revealed the architecture of the SMC5/6 complex and elucidated the molecular mechanisms by which ATPase activity, DNA-binding modules, and SUMO-and ubiquitin-mediated regulatory pathways cooperate to maintain genome integrity. Extensive evidence has further demonstrated that SMC5/6 functions as a broad-spectrum antiviral restriction factor by recognizing and silencing episomal viral genomes, whereas diverse viruses have evolved strategies to evade or counteract its activity. In addition, dysfunction of the SMC5/6 complex has been associated with cancer, developmental disorders, and genome instability syndromes. This review summarizes recent advances in the structure, molecular mechanisms, antiviral functions, and disease relevance of the SMC5/6 complex, providing a basis for a deeper understanding of its diverse biological functions and potential applications.