The tale of a tail: histone H4 acetylation and the repair of DNA breaks

摘要

The ability of cells to detect and repair DNA double-strand breaks (DSBs) within the complex architecture of the genome requires co-ordination between the DNA repair machinery and chromatin remodelling complexes. This co-ordination is essential to process damaged chromatin and create open chromatin structures which are required for repair. Initially, there is a PARP-dependent recruitment of repressors, including HP1 and several H3K9 methyltransferases, and exchange of histone H2A.Z by the NuA4-Tip60 complex. This creates repressive chromatin at the DSB in which the tail of histone H4 is bound to the acidic patch on the nucleosome surface. These repressor complexes are then removed, allowing rapid acetylation of the H4 tail by Tip60. H4 acetylation blocks interaction between the H4 tail and the acidic patch on adjacent nucleosomes, decreasing inter-nucleosomal interactions and creating open chromatin. Further, the H4 tail is now free to recruit proteins such as 53BP1 to DSBs, a process modulated by H4 acetylation, and provides binding sites for bromodomain proteins, including ZMYND8 and BRD4, which are important for DSB repair. Here, we will discuss how the H4 tail functions as a dynamic hub that can be programmed through acetylation to alter chromatin packing and recruit repair proteins to the break site.