DESI1 (desumoylating isopeptidase 1) is a protease that removes SUMO conjugates from substrate proteins through isopeptidase activity, representing a distinct class of deSUMOylases separate from SENP family proteases 1. DESI1 deconjugates SUMO1, SUMO2, and SUMO3 from target proteins including ZBTB46, and also exhibits palmitoyl protein thioesterase activity. Additionally, DESI1 collaborates with UBQLN4 in exporting ubiquitinated proteins from nucleus to cytoplasm. Mechanistically, DESI1 regulates cell division by controlling FoxM1 transcriptional activity and spindle assembly checkpoint (SAC) function. DESI1 knockdown accelerates cell cycle progression and increases abnormal chromosome 22 through reduced Aurora B expression at metaphase chr22 2. This deSUMOylation activity is catalytically essential, as catalytically inactive DESI1 cannot rescue these phenotypes. Clinically, DESI1 has dual roles in cancer biology. Both decreased and increased DESI1 expression correlate with poor prognosis in certain cancer types 2. DESI1 knockdown reduces vincristine sensitivity by promoting mitotic slippage, suggesting implications for chemotherapy response. DESI1 also associates with colon adenocarcinoma progression through miR-135b-5p regulation 3, and altered DESI1 expression appears linked to epithelial-mesenchymal transition in lung cancer under hypoxic-reoxygenation stress 4.