Histone modifications: crucial elements for damage response and chromatin restoration

Abstract

Eukaryotic genomes are packaged into chromatin from repeated nucleosome arrays in which DNA sequences wrap around histones. Chromatin organization has profound influence on DNA-templated processes such as transcription, DNA replication, and repair. Recent studies have also revealed chromatin dynamics as an active contributor to diverse DNA damage responses (DDR). Here, we review recent progress in histone modification related to DDR and post-repair chromatin restoration at the sites of DNA damage. We discuss how the timing and features of histone modifications would provide the initial as well as the final guidance for DDR, and the prospect that modifications may challenge the epigenetic stability of repaired cells and serve as damage memory in chromatin.

Fig. 1

Temporal interplay of histone modifications before and after DNA repair. Upon initial DNA damage, nucleosomal histones are subjected to various PTMs: H3 and H4 acetylation by TIP60 HAT, H2AX phosphorylation by ATM/ATR, γH2AX and H2A ubiquitination by RNF8, or H3 and H4 ubiquitination by DDB-CULA-ROC1. These modifications may cause nucleosome disassembly, or histone eviction, and facilitate access of the repair nanomachines to DNA lesions. When DNA repair is complete, repair-dependent chromatin assembly restores the original nucleosome density. The histones with new epigenetic marks i.e., the acetylated histone H3, the ubiquitinated H2A, and possibly the histones with other modifications are incorporated into newly assembled chromatin at the damage sites. After chromatin is restored, the checkpoint is terminated and cells resume cycling. Some PTMs would be eliminated and others retained to serve as a memory of damage, potentially challenging the epigenetic stability of the cells having undergone repair. The symbols with “P”, “Ub”, “Ac” and “Me” represent phospho, ubiquitin, acetyl and methyl groups, respectively.