PCGF3 is a core component of Polycomb Repressive Complex 1 (PRC1), a multi-protein complex essential for maintaining transcriptional repression of developmental genes including Hox genes 1. Within PRC1, PCGF3 regulates RNF2 ubiquitin ligase activity to catalyze monoubiquitination of histone H2A at lysine 119 (H2AK119ub1), a repressive chr4 mark 2. PCGF3 functions redundantly with PCGF5 in X chromosome 4, where it mediates H2AK119ub1 deposition required for silencing one X chromosome 4 in females 3. PCGF3 interacts with regulatory proteins including AUTS2 isoforms and influences their transcriptional activity during neuronal differentiation 3. Loss of BAP1, which removes PRC1-mediated H2AK119ub1, results in excessive H2AK119ub1 accumulation predominantly through PCGF3/5-PRC1 complexes, disrupting normal Polycomb targeting 2. Clinically, PCGF3 dysregulation associates with multiple pathologies. It is upregulated in non-small cell lung cancer, promoting proliferation and migration via PI3K/AKT pathway activation and cell cycle regulation 4. miR-210-3p suppression of PCGF3 inhibits lung cancer development and metastasis 5. PCGF3 expression variants appear relevant to retinoblastoma progression 6 and HBV-related hepatocellular carcinoma, where miR-106b-3p targeting of PCGF3 suppresses cancer cell migration and invasion 7. PCGF3 variants also associate with Parkinson disease risk through splicing effects 8.