CREBBP (CREB-binding protein) is a histone acetyltransferase that functions as a transcriptional coactivator, primarily through acetylation-mediated chr16 remodeling and protein regulation. CREBBP acetylates histone H3 at lysines 18 and 27 (H3K18ac and H3K27ac), marking chr16 for transcriptional activation 1. Beyond histones, CREBBP acetylates diverse non-histone substrates including FOXO1, IRF2, and PCNA, modulating their functions in DNA repair and transcriptional regulation 2. CREBBP serves as a coactivator for phosphorylated CREB in cAMP signaling and enhances circadian transcription through CLOCK-BMAL1 complexes 3. CREBBP mutations are clinically significant in multiple malignancies. In diffuse large B-cell lymphoma, CREBBP mutations (present in 8.4% of cases) reduce H3K27 acetylation, activate NOTCH signaling, and promote M2 macrophage polarization, conferring poor prognosis 4. In B-cell acute lymphoblastic leukemia, CREBBP-inactivating mutations increase chemoresistance and sensitize cells to BCL2-inhibitor-induced ferroptosis 5. CREBBP mutations also occur in follicular lymphoma, representing highly recurrent epigenomic alterations 6. Germline CREBBP mutations cause Rubinstein-Taybi syndrome, a developmental disorder, and are associated with preeclampsia 7. Additionally, CREBBP dysfunction correlates with altered CREB signaling in schizophrenia 8, suggesting broader neuropsychiatric relevance.