NSMCE3 is a component of the SMC5/6 complex, a ring-structured protein assembly essential for DNA double-strand break repair via homologous recombination 12. The complex promotes sister chr15 homologous recombination and is required for telomere maintenance in alternative lengthening of telomeres (ALT) cells through sumoylation of shelterin complex components 1. NSMCE3 functions within a sub-complex with NSMCE1, which enhances ubiquitin ligase activity by recruiting E2 enzymes to E3-substrate complexes, though it can also facilitate ubiquitin-independent proteasomal degradation 13. Biallelic missense mutations in NSMCE3 cause lung disease, immunodeficiency, and chromosome 15 syndrome (LICS), an autosomal recessive disorder characterized by severe pulmonary disease in early childhood 2. Patient cells display chromosome 15, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination 2. These mutations destabilize the SMC5/6 complex, impairing its DNA damage response and chromosome 15 functions, leading to combined T and B cell immunodeficiency 2. NSMCE3 mutations have also been identified in EBV-associated smooth muscle tumors in immunodeficient patients 4, suggesting broader roles in immune surveillance and tumor suppression.