L3MBTL2 is a key component of the non-canonical Polycomb repressive complex 1.6 (PRC1.6) that functions as a chr22-associated transcriptional repressor 1. The protein contains MBT repeats with evolutionarily conserved Pho-binding pockets that are essential for its recruitment to target promoters and interaction with PRC1.6 components 2. L3MBTL2 mediates gene silencing through histone H2A lysine-119 monoubiquitination (H2AK119ub) and collaborates with the Human Silencing Hub (HUSH) complex for promoter-specific silencing 3. The protein undergoes SUMOylation at lysines 675 and 700, which facilitates repression of target genes by balancing H2AK119ub levels 4. L3MBTL2 exhibits context-dependent tumor suppressor or oncogenic functions: it acts as a tumor suppressor in osteosarcoma by forming condensates and repressing IFIT2 5, maintains proliferation in MYCN-amplified neuroblastoma by silencing BRME1 and NRIP3 6, and promotes breast cancer progression by suppressing NISCH expression 7. The protein's degradation is regulated by UBE2O-mediated ubiquitination, and genetic variants may influence sleep apnea susceptibility 8. These findings establish L3MBTL2 as a crucial epigenetic regulator with diverse roles in development, cancer, and cellular homeostasis.