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

Abstract

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.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.

Cell-type-specific epigenomic variations associated withBRCA1mutation in pre-cancer human breast tissues

“…For instance, DNA replication-independent nucleosome assembly and organization can only occur with histone variant 3.3, which is part of the DNA repair pathway (Ahmad and Henikoff 2002;Frey et al 2014). In addition, histone H4 acetylation also opens up the chromatin for easier access to damaged regions (Dhar et al 2017). In contrast, we largely see ontologies associated with cell motility and adhesion in BCs.…”

Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells

“…It is possible that the chromatin remodeling activity of Chd1 facilitates access of Atm to its target site on H2A.X, or that other interactors of Chd1 promote Atm activity towards H2A.X. For example, Chd1 also interacts with PARP1 and the histone acetyltransferase Tip60 (data not shown), and both histone ADP ribosylation and acetylation are involved in chromatin relaxation at DNA repair sites 28,29 . Further biochemical studies of how the activity of Atm and other aspects of DNA repair are modulated by Chd1 will shed light on the mechanisms by which stem and progenitor cells can undergo hypertranscription while preserving DNA integrity.…”

Lysine-specific post-translational modifications of proteins in the life cycle of viruses

“…The modifications of positively charged amino acids (such as arginine and lysine) play an important role in the regulation of folding and biochemical activity of cellular proteins, PTMs such as ubiquitination, sumoylation, acetylation, methylation, therefore introduce an additional level of intracellular regulation for cellular signaling proteins. For example, lysine-specific modifications that target proteins affect key cellular processes such as proteasome degradation [1,2], repair of double-strand DNA breaks [3][4][5][6], regulation of gene expression [7,8] [9][10][11][12][13], signaling pathways [14][15][16][17][18] immune response [19,20], cell cycle [21,22] and metabolism [23,24].…”