RNF20 is an E3 ubiquitin ligase that primarily catalyzes histone H2B monoubiquitination (H2Bub1) and plays critical roles in transcriptional regulation, DNA damage response, and cellular homeostasis 1. As part of the RNF20/RNF40 complex, it functions as a tumor suppressor by regulating p53-dependent gene transcription and mRNA splicing, specifically controlling expression of tumor suppressor genes like p21 and PUMA 2. RNF20 mediates RNA polymerase II promoter-proximal pausing at highly paused genes involved in VEGFA signaling, stress response, and cell cycle control, which is crucial for angiogenesis regulation 3. Beyond its ligase activity, RNF20 acts as a recombination mediator, promoting Rad51 filament formation during homologous recombination repair while counteracting helicases that disrupt DNA repair 4. Clinically, RNF20 haploinsufficiency increases lung tumor incidence through metabolic rewiring via HIF1α 5, and its expression is reduced in congenital heart disease patients, where it normally prevents endothelial-to-mesenchymal transition and maintains proper cardiac development 6. RNF20 also regulates immune homeostasis by serving as a negative regulator of Foxp3 in regulatory T cells 7.