Heritability is the manifestation of genetic and epigenetic traits. Genetic traits include normal and mutated (alternative) DNA sequences. Epigenetic effects are chromosomal in origin but occur outside the DNA sequence; these include DNA methylation, RNA-interference (RNAi), histone modification, and chromatin remodeling. Assays now exist for the first two of these four, histone modifications are becoming more understood, and still the most mysterious is chromatin remodeling. If one combines genetic and epigenetic events with environmental effects––plus the as-yet-fully understood phenomena of “the patterns of pleiotropy, dominance, decanalization, and epistasis––all of this together is termed the “genetic architecture” of a human or any other organism. Ultimately, it is the genetic architecture of each cell that is responsible for the phenotype (multifactorial trait) of the organism––whether it is schizophrenia, type-2 diabetes, Pb-induced mental retardation, or an adverse drug reaction such as acute pancreatitis or cardiac arrhythmia.
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) which catalyze addition and removal of acetyl groups on lysine residues, a post-translational modification important for 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. Authors [see attached report] analyze how acetylation signaling impacts the DDR in the context of cancer and its treatment(s). 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.
PLoS Genet Sept 2o16; 12: e1006272