RNF40 (Ring Finger Protein 40) is an E3 ubiquitin ligase that forms a heterodimer with RNF20 to catalyze histone H2B monoubiquitylation at lysine 120 (H2Bub1), a critical epigenetic modification regulating gene transcription and genome stability 12. The RNF20/RNF40 complex binds nucleosomal DNA and positions the E2 enzyme for site-specific ubiquitin transfer to H2B 3. This modification is essential for DNA damage repair, where H2Bub1 facilitates recruitment of repair proteins to double-strand break sites 1. RNF40 functions as both tumor suppressor and oncogene depending on cellular context - it suppresses intestinal inflammation through vitamin D receptor signaling 4 but promotes aggressive behavior in triple-negative breast cancer by supporting glycolysis and cancer stem cell properties 5. Beyond histone modification, RNF40 regulates cell cycle progression through centrosome maturation, undergoing cell cycle-dependent acetylation-to-phosphorylation transitions that control PLK1 recruitment and proper chromosome 16 6. The protein's dual roles in transcriptional regulation and cell division make it a critical epigenetic regulator with significant implications for cancer development and genome stability.