On May 12, 2025, in Current Opinion in Structural Biology, researchers from the Institute of Biophysics of Chinese Academy Sciences, have reviewed the intricate molecular choreography that ensures faithful transmission of genetic and epigenetic information during eukaryotic DNA replication.

During DNA replication, the chromatin structure is transiently dismantled, which presents a significant challenge to the cell: how to preserve the original epigenetic landscape and maintain genome integrity? Central to this process is replication-coupled (RC) nucleosome assembly, which requires the coordinated handling of newly synthesized and recycled histones.

Histone chaperones, which are specialized a group of proteins that escort histones through their cellular journey, have emerged as central players in this delicate operation. The assembly of replication-coupled (RC) nucleosomes can be separated into two distinct pathways based on the origin of histones: (1)The de novo assembly pathway of newly synthesized histones, mediated by the histone chaperone chromatin assembly factor 1 (CAF-1) complex; and (2)The recycling pathway of parental histones, in which the histone chaperone facilitates chromatin transcription (FACT) complex plays a key role.

This review systematically summarizes the latest progress in the structural biology of RC nucleosome assembly, with a focus on the de novo assembly mechanism of newly synthesized histone H3-H4 tetrasomes by the CAF-1 complex, as well as the molecular mechanism by which the FACT complex recycles parental histone hexamers.

Structural studies of RC chromatin assembly not only have revealed the molecular events underlying the inheritance of epigenetic information, but also offer new insights for the development of anticancer drugs targeting the chromatin assembly process.

The review furthermore discussed the interaction mechanisms between histone chaperones and the replication machinery, expanding the classical role of molecular chaperones to include their function within the DNA replisome.

Finally, the review pointed out future directions and proposed potential strategies to further explore the "coupling" between DNA replication and chromatin assembly.

This review deepens our understanding of chromatin dynamics during replication.

Figure. Histone Chaperone-Mediated Replication-Coupled Chromatin Assembly Pathway

(Image by XU Ruiming's Group)

Article link: https://doi.org/10.1016/j.sbi.2025.103059

Contact: XU Ruiming

Institute of Biophysics, Chinese Academy of Sciences

Beijing 100101, China

E-mail: rmxu@ibp.ac.cn

(Reported by Prof. XU Ruiming's Group)