Abstract
Chromatin-based DNA damage response (DDR) pathways are fundamental for preventing genome and epigenome instability, which are prevalent in cancer. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the addition and removal of acetyl groups on lysine residues, a post-translational modification important for the DDR. Acetylation can alter chromatin structure as well as function by providing binding signals for reader proteins containing acetyl-lysine recognition domains, including the bromodomain (BRD). Acetylation dynamics occur upon DNA damage in part to regulate chromatin and BRD protein interactions that mediate key DDR activities. In cancer, DDR and acetylation pathways are often mutated or abnormally expressed. DNA damaging agents and drugs targeting epigenetic regulators, including HATs, HDACs, and BRD proteins, are used or are being developed to treat cancer. Here, we discuss how histone acetylation pathways, with a focus on acetylation reader proteins, promote genome stability and the DDR. We analyze how acetylation signaling impacts the DDR in the context of cancer and its treatments. Understanding the relationship between epigenetic regulators, the DDR, and chromatin is integral for obtaining a mechanistic understanding of genome and epigenome maintenance pathways, information that can be leveraged for targeting acetylation signaling, and/or the DDR to treat diseases, including cancer.
Highlights
Genome maintenance relies on the precise replication and repair of our genetic information
I-CBP112 displayed a synergistic cytotoxic effect with JQ1, as more γH2AX foci were observed in co-treated cells (Table 2). These results suggest that CBP/p300 and BRD4 may function in different DNA damage response (DDR) pathways, providing selectivity for these inhibitors in either CBP/p300 mutant cells with BRD4 inhibitors or vice versa
Mounting evidence highlights the crucial function of acetylation signaling in regulating the DDR and maintaining genome integrity
Summary
Genome maintenance relies on the precise replication and repair of our genetic information. Chromatin PTMs are dynamically regulated in response to DNA damage both locally at the lesion site and globally where they perform several functions [18,19,20,21,22] These include modulating chromatin structure at DNA damage sites and across the genome to facilitate the DDR, including signaling [22,23,24], repair [25], and transcriptional responses [26,27]. Another fundamental role of PTMs is to provide docking sites for the recognition and accumulation of DDR factors at damage sites where they orchestrate DDR functions. We consider DDR-related acetylation signaling in cancer and its potential impact on cancer therapies
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