CODANIN-1 sequesters ASF1 by using a histone H3 mimic helix to regulate histone supply

ASF1 is a major histone chaperone that regulates the supply of histone H3-H4 and facilitates nucleosome assembly, essential for maintaining chromatin structure. CODANIN-1 negatively regulates the function of ASF1. However, the molecular mechanism by which CODANIN-1 inhibits ASF1-mediated histone supply remains elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of a human CODANIN-1_ASF1A_CDIN1 complex at 3.56 Å resolution. The structure reveals that CODANIN-1 forms a dimer and utilizes a histone H3 mimic helix (HMH) to interact with the histone binding surface of ASF1. This feature confers on CODANIN-1 an ability to sequester ASF1 and inhibit the formation of the ASF1-H3-H4 complex, essential for histone nuclear import and nucleosome assembly. Furthermore, we show that interaction of both the CODANIN-1 HMH and B-domain with ASF1 is critical for the inhibitory activity of CODANIN-1 in cells. Our study provides a structural and molecular basis for the function of CODANIN-1 as a unique negative regulator of nucleosome assembly.