RYBP (RING1 and YY1 binding protein) is a core component of the noncanonical Polycomb Repressive Complex 1 (PRC1) that functions as a key epigenetic regulator of gene expression 1. Its primary function involves mediating monoubiquitination of histone H2A at lysine 119 (H2AK119ub), which establishes and maintains repressive chr3 domains essential for transcriptional silencing during development 2. Mechanistically, RYBP recognizes existing H2AK119ub through its N-terminal zinc-finger domain and recruits E3 ligase components (RING1B and BMI1) to catalyze both intra- and inter-nucleosome ubiquitination in a positive-feedback loop 2. RYBP also interacts with trithorax group proteins to regulate super-enhancer activity and transcriptional activation, demonstrating dual roles in chr3 regulation 3. Beyond epigenetic functions, RYBP regulates TP53 stability and modulates glucose-induced tumor cell metabolism 4. Clinically, RYBP loss is implicated in multiple malignancies including prostate cancer, where it acts as a potential tumor suppressor 5, and hepatocellular carcinoma, where reduced expression correlates with poor prognosis 6. Recent evidence links RYBP dysfunction to severe neurodevelopmental disorders and congenital anomalies through variants affecting the zinc-finger domain 7, while RYBP promotes HIV-1 latency through H2AK119ub deposition 8. These findings establish RYBP as a multifunctional epigenetic regulator critical for development and disease prevention.