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

Area of Science:

• Molecular biology
• Structural biology
• Chromatin dynamics

Background:

• ASF1 is a key histone chaperone essential for nucleosome assembly, DNA replication, and transcription.
• CODANIN-1 acts as a negative regulator of ASF1 function, but its inhibitory mechanism is not well understood.

Purpose of the Study:

• To elucidate the molecular mechanism by which CODANIN-1 inhibits ASF1-mediated histone supply.
• To determine the structural basis of the CODANIN-1-ASF1 interaction.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structure of the human CODANIN-1_ASF1A complex.
• Structural analysis of the complex to identify interaction interfaces and mechanisms of inhibition.

Main Results:

• The cryo-EM structure of the human CODANIN-1_ASF1A complex was determined at 3.75 Å resolution.
• CODANIN-1 forms a dimer, with each monomer binding two ASF1 molecules via its B-domains and histone H3 mimic helices (HMHs).
• This interaction inhibits ASF1/H3-H4 complex formation and sequesters ASF1 in the cytoplasm, preventing nucleosome assembly.

Conclusions:

• The study provides a structural and molecular explanation for CODANIN-1's negative regulatory role on ASF1.
• CODANIN-1 inhibits nucleosome assembly by hijacking ASF1's interaction sites for histones and other chaperones.