RBBP5 is a core scaffolding protein of histone lysine methyltransferase complexes that catalyze H3K4 methylation, a hallmark of active gene transcription. As part of MLL1/MLL and SET1 complexes, RBBP5 associates with WDR5 and ASH2L to stimulate the methyltransferase activities of KMT2A, KMT2B, KMT2C, KMT2D, SETD1A, and SETD1B 12. Structurally, RBBP5 makes extensive nucleosome contacts through its WD40 propeller and C-terminal regions, facilitating access to histone H3 tails for efficient methylation 3. An internal interaction within RBBP5 maintains complex compaction and nucleosome recognition 4. In developmental contexts, RBBP5 regulates H3K4 methylation at key developmental loci, particularly along the neural lineage in embryonic stem cells. Loss-of-function RBBP5 variants cause syndromic neurodevelopmental disorders characterized by microcephaly, global developmental delay, and intellectual disability 5. Clinically, RBBP5 phosphorylation at Ser497 by HKDC1 promotes hepatocellular carcinoma progression through enhanced H3K4me3 deposition and cell cycle gene activation 6. RBBP5 also functions in cancer-associated fibroblasts where its activity via KMT2 regulates tumor microenvironment-mediated cancer cell migration and invasion 7.