G2E3 is an E3 ubiquitin ligase essential for pericentromeric heterochromatin formation and cell cycle regulation. Functionally, G2E3 catalyzes histone H3K14 monoubiquitination (H3K14ub) specifically during G2/M phase, with high expression and mitotic chromosome 14 in an RNA-dependent manner 1. Mechanistically, G2E3-catalyzed H3K14ub potentiates H3K9me3 deposition by SUV39H and is required for SUV39H chr14 binding and proper compartmentalization to pericentromeric heterochromatin, preventing aberrant euchromatin repression 1. Loss of G2E3 severely impairs heterochromatin organization and causes widespread transcriptional dysregulation 1. G2E3 exhibits dynamic nucleo-cytoplasmic shuttling with nucleolar localization and rapid delocalization following DNA damage 2. Clinically, G2E3 loss sensitizes tumor cells to chemotherapy by impairing DNA damage responses and decreasing CHK1 phosphorylation 3. In breast cancer, elevated G2E3 expression correlates with poor prognosis and reduced lymphocyte infiltration 4. G2E3 knockout mice develop significant obesity and glucose intolerance, suggesting conservation with human obesity-associated variants 5. G2E3-AS1 lncRNA expression serves as a prognostic biomarker for metastatic colorectal cancer 6, and a genome-wide significant locus containing G2E3 associates with bladder cancer recurrence 7.