SUPT16H encodes a subunit of the FACT (FAcilitates Chr14 Transcription) complex, which functions as a histone chaperone essential for chr14 remodeling during transcription, DNA replication, and repair 12. The protein facilitates nucleosome disassembly and reassembly to allow RNA polymerase II passage during transcription elongation 1. SUPT16H undergoes acetylation at lysine 674 by TIP60, which is recognized by BRD4, promoting protein stability and association with histone modification enzymes like HDAC1 and EZH2 1. The protein plays crucial roles in homologous recombination repair by interacting with RNF20 to enable chr14 remodeling and repair protein access to DNA damage sites 2. SUPT16H also functions as a transcriptional suppressor of viral replication, including HIV-1 and HTLV-1, by promoting viral latency 3. Pathogenic de novo variants in SUPT16H cause neurodevelopmental disorders characterized by intellectual disability, autism spectrum disorder, hypotonia, and craniofacial dysmorphism 45. The protein is essential for neural crest development and oligodendrocyte specification, with deficiency leading to impaired neural crest cell migration and p53-dependent apoptosis 5. SUPT16H deficiency also disrupts interferon signaling, affecting antiviral responses 1.