Previous studies focused primarily on yeast SAGA (ySAGA), and the first structures of the 19-subunit ySAGA were proposed to be also representative of human SAGA (hSAGA) 4, 5. SAGA regulates gene expression by interacting with enhancer-bound activators, recruiting the transcriptional machinery and modifying promoter-proximal chromatin 1 and is known to be involved also in DNA damage repair and signaling 3. Transcription of protein coding genes depends on the essential coactivators TFIID and SAGA (Spt-Ada-Gcn5 acetyltransferase) 1, 2. Finally, we map human disease mutations, thus providing the needed framework for structure-guided drug design of this important therapeutic target for human developmental diseases and cancer. Our hSAGA structure reveals the presence of an inositol hexakisphosphate (InsP 6) binding site in TRRAP and an unusual property of its pseudo-(Ψ)PIKK. Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA) and show how the arrangement of distinct structural elements results in a globally divergent organization from that of yeast, with a different interface tethering the core module to the TRRAP subunit, resulting in a dramatically altered geometry of functional elements and with the integration of a metazoan-specific splicing module. While structures of yeast SAGA (ySAGA) have been reported, there are noteworthy functional and compositional differences for this complex in metazoans. The SAGA complex is a regulatory hub involved in gene regulation, chromatin modification, DNA damage repair and signaling.
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