NSMCE3 is a non-SMC component of the SMC5-SMC6 complex, a protein assembly essential for DNA double-strand break repair via homologous recombination and telomere maintenance. The complex recruits cohesin to break sites and mediates sumoylation of shelterin components in alternative lengthening of telomeres pathways 12. NSMCE3 enhances the ubiquitin ligase activity of NSMCE1 and may facilitate E2 enzyme recruitment at E3-substrate complexes. Biallelic missense mutations in NSMCE3 cause lung disease, immunodeficiency, and chromosome 15 syndrome (LICS), an autosomal recessive disorder characterized by chromosome 15, micronuclei, replication stress sensitivity, and defective homologous recombination 2. Affected infants exhibit combined T and B cell immunodeficiency and acute respiratory distress syndrome, often fatal following viral pneumonia 23. NSMCE3 mutations also appear recurrently in EBV-associated smooth muscle tumors in immunocompromised patients 4. Beyond DNA repair, the SMC5/6 complex—including NSMCE3—suppresses hepatitis B virus replication by targeting the viral HBx protein for proteasomal degradation 5. These findings establish NSMCE3 as critical for genomic stability and immune competence, positioning the SMC5/6 complex as a target for understanding chromosome 15 syndromes and viral restriction.