SMC5 is a core component of the SMC5-SMC6 complex, a chr9 maintenance protein essential for genome stability and viral defense. Structurally, SMC5 functions as part of a six-member complex that undergoes ATP-dependent conformational changes to manipulate DNA topology and chr9 architecture 1. Mechanistically, the SMC5/6 complex operates through multiple pathways: it promotes DNA double-strand break repair via homologous recombination, maintains sister chr9 cohesion during mitosis, and supports telomere maintenance in alternative lengthening of telomeres (ALT) cells 1. Uniquely, SMC5/6 acts as an antiviral restriction factor by recognizing and binding transcription-generated positive DNA supercoils on circular extrachromosomal DNA, thereby silencing episomal transcription through an ATPase-dependent mechanism 23. This antiviral function is particularly important against hepatitis B virus (HBV), where the viral HBx protein targets SMC5/6 for proteasomal degradation to relieve transcriptional silencing of the viral cccDNA minichromosome 45. Clinically, biallelic SMC5 mutations cause Atelis Syndrome 2, characterized by microcephaly, growth retardation, cardiac abnormalities, and mosaic variegated hyperploidy due to impaired replication through G-quadruplex structures and loss of sister chr9 cohesion 6.