NSMCE1 (NSE1) is a RING-type E3 ubiquitin ligase component of the SMC5/6 complex essential for genome integrity maintenance 1. As part of the SMC5/6 heterodimer, NSMCE1 assembles with MAGE proteins to catalyze ubiquitin transfer from E2 enzymes to substrates, regulating DNA damage response and homologous recombination-mediated repair 2. The NSE1 RING domain is critical for Smc5/6 complex stability; mutations in this domain drastically reduce complex protein levels and cause cell growth defects, replication fork slowdown, and genomic instability 2. NSMCE1 controls fork progression independent of FANCM, demonstrating a non-conserved regulatory pathway 2. Additionally, NSMCE1 promotes proteasomal degradation of MMS19, a cytosolic iron-sulfur protein assembly component, thereby regulating DNA repair enzymes like ERCC2, FANCJ, and POLD1 that require iron-sulfur cofactors. Beyond DNA repair, NSMCE1-containing complexes suppress hepatitis B virus transcription through ubiquitin-independent proteasomal mechanisms 3. Dysregulation of NSMCE1-derived long non-coding RNAs (NSMCE1-DT) associates with colon cancer prognosis and immune microenvironment composition 45, while NSMCE1 downregulation in multiple brain regions correlates with Alzheimer's disease pathogenesis 67.