SMC6 is a core component of the SMC5-SMC6 complex, a multifunctional protein machine essential for genome stability. Mechanistically, SMC6 functions in three distinct processes: (1) DNA repair through homologous recombination at double-strand breaks, where it recruits the cohesin complex and prevents accumulation of unscheduled recombination intermediates 1; (2) telomere maintenance via recombination in alternative lengthening of telomeres cells through SUMO-mediated modifications of shelterin components 2; and (3) transcriptional silencing of extrachromosomal DNA, including viral genomes, through a three-step process involving ATPase-dependent DNA entrapment, PML body recruitment, and Nse2-dependent silencing 3. SMC6 recognizes transcription-induced positive DNA supercoils as a mechanism to distinguish episomal from chr2 DNA 4. Disease relevance is substantial: SMC6 mutations appear in cancer genomes, with noncoding mutations near its regulatory regions potentially serving as drivers 5. The complex is synthetically lethal with APOBEC3A activity, as SMC6-depleted cells accumulate genotoxic damage during replication stress 6. Clinically, hepatitis B virus targets SMC6 for degradation to enable viral transcription, identifying SMC6 as a host restriction factor 7, while therapeutic stabilization of SMC6 could inhibit both HBV replication and APOBEC3A-driven mutagenesis in cancer.