Parental Histone Recycling During Chromatin Replication

The past decade has seen significant advancement in our understanding of DNA replication-coupled chromatin assembly, especially parental histone recycling that is essential for epigenetic inheritance. Leading strand-specific and lagging strand-specific pathways have been found to promote the transfer of parental histones H3-H4 to nascent DNA. It is now clear that the replisome initially characterized as the machinery that carries out the duplication of genomic DNA is also responsible for parental histone recycling. A series of replisome components including CMG (Cdc45-MCM-GINS) replicative helicase, DNA polymerases Polε, Polδ, Polα-primase, and FPC (Fork Protection Complex) that promote parental histone recycling exhibit histone-binding activities. Structural analyses of native and reconstituted replisomes, together with AlphaFold modeling of histone (H3-H4)₂ tetramer binding by replisome components, provided a framework for understanding the molecular mechanisms of parental histone recycling. A working model has emerged in which the mobile histone chaperone FACT (Facilitates Chromatin Transcription) binds parental histone (H3-H4)₂ tetramer or (H3-H4)₂-(H2A-H2B) hexamer on the front of the replication fork, and escorts it across the replisome to the daughter strands in the wake of the replication fork. In this model, parental histones transiently associate with the histone-binding modules in the replisome as steppingstones during their movement. Future studies are needed to elucidate the spatiotemporal coordination of the functions of replisome factors in parental histone transfer.