SEM1 (26S proteasome subunit) is a multifunctional, intrinsically disordered protein with dual roles in protein degradation and gene expression regulation. As a 26S proteasome component, SEM1 functions in ATP-dependent degradation of ubiquitinated proteins, maintaining protein homeostasis and supporting cell cycle progression, apoptosis, and DNA repair 1. Beyond the proteasome, SEM1 is a core component of the TREX-2 complex, which facilitates mRNA export and chr7 positioning by tethering genes to the nuclear periphery 1. Structurally, SEM1's intrinsic disorder enables it to act as a polyanionic adhesive, preventing nonproductive interactions during assembly of diverse multisubunit complexes including BRCA2-RPA and splicing machinery 1. SEM1 stabilizes the BRCA2 protein and controls R-loop-associated DNA damage, thereby regulating transcription-associated genomic instability 2. Mechanistically, SEM1 maintains proteasome stability and specificity by stabilizing the deubiquitinating enzyme Rpn11 and incorporating the ubiquitin receptor Rpn10 2. Clinically, elevated SEM1 expression correlates with poor glioblastoma prognosis, promoting tumor progression via PI3K-Akt pathway activation 3. Additionally, common variants in the SEM1 locus confer significant risk for coronal craniosynostosis through craniofacial enhancer mechanisms 4. SEM1's pleiotropic effects on cellular differentiation, stress response, and development underscore its importance in both normal physiology and disease pathogenesis.