H4S47 phosphorylation. Ryu et al.

During DNA replication in the S phase, the parental nucleosome is disassembled ahead of the replication fork, and then transferred onto either leading or lagging daughter strands behind the fork to reconstitute the chromatin structure. These processes can be completed by the coordination of chromatin remodeling factors, including histone chaperones, covalent histone-modifying enzymes, and ATP-dependent chromatin remodeling complexes. Accumulating evidence has revealed that specific post-translational modifications (PTMs) on histone proteins are relevant to chromatin remodeling factors for proper DNA replication. Histone deacetylases (HDACs) are chromatin-remodeling factors that remove acetyl groups to form compact chromatin structures behind the replication fork. The loss of HDAC activity (e.g., the absence of HDACs or treatment with HDAC inhibitors) causes hyper acetylation of histones, thereby disrupting the heterochromatin structure. Such abnormal alterations of the chromatin structure in the S phase cause genome instability, such as aberrant cell mitosis. These findings demonstrate that the HDACs are involved in chromatin maturation in the S phase. The well-characterized histone modifications in the DNA replication process include the acetylation on lysine residues in the N-terminal tail of histones H3 and H4, which have roles in chromatin deposition and assembly followed by maturation of replicating chromatin structure. Among the modifications, histone H4K16 acetylation (H4K16ac) plays a critical role in regulating the chromatin structure. Given the information indicating that histone H4 has very low sequence variation across species, histone H4K16ac understandably has important role(s) in regulating chromatin structure. The status of H4K16ac directly modulates the higher-order structure of chromatin. The disruption of H4K16ac is involved in the formation of compact chromatin. In contrast, the acetylated status of H4K16 forms open chromatin in the S phase. The chromatin structure matures in late S and G2 phases, and then is tightly condensed to produce the mitotic chromosome. Because of the role of H4K16ac in chromatin structure, alteration of chromatin structure by the status of H4K16ac appears to promote not only S phase entry but also S phase exit (or mitotic entry). Therefore, the balance of H4K16ac expression during the cell cycle is possibly essential for genome stability.