ATXN7L3B is a cytoplasmic protein that negatively regulates the SAGA complex's deubiquitinase (DUB) module through competitive binding to ENY2 1. Unlike its homolog ATXN7L3, ATXN7L3B localizes in the cytoplasm where it sequesters ENY2, preventing its nuclear association with ATXN7L3 and USP22, thereby increasing histone H2B monoubiquitination (H2Bub1) levels and reducing DUB activity toward substrates 1. This mechanism regulates gene expression, particularly estrogen receptor target genes 1. ATXN7L3B has emerging disease relevance across multiple systems. In hepatocellular carcinoma, ATXN7L3B expression correlates negatively with patient survival and promotes cancer stemness; metformin downregulates ATXN7L3B to inhibit HCC tumor-initiating ability 2. Neurologically, deletions encompassing ATXN7L3B associate with neurodevelopmental delay and cerebellar ataxia 3, and balanced translocations disrupting this locus cosegregate with vascular phenotypes and progressive neurological symptoms including chr12 headache and tremor 4. ATXN7L3B expression is upregulated in microglia during neuroinflammation in multiple sclerosis 5 and is downregulated in MCM3AP-associated neuropathy with intellectual disability 6. A colorectal cancer-associated SNP (rs590352) in ATXN7L3B shows gender-specific associations 7. These findings suggest ATXN7L3B functions as a regulatory hub affecting cancer stemness, neurological development, and neuroinflammation.