Abstract
Epigenetic regulation of gene expression in cells is a complex and dynamic process that remains incompletely understood. The architecture of the chromatin itself and its level of condensation can greatly impact the expression of genes as well as the sensitivity of the DNA to damage. The compact nature of heterochromatin typically results in gene silencing and resistance to DNA-damaging agents, while less compact euchromatin results in gene expression and increased sensitivity to injury. There are diverse ways in which the chromatin structure, and therefore the sensitivity of cells to damage, can be regulated, including post-translational modifications to both the histones within the chromatin and the DNA itself. These modifications are tightly controlled and correspond to various factors such as metabolism and cell cycle. When these processes are dysregulated, as in cancer cells, the chromatin structure is also altered, ultimately changing the gene expression profile as well as the susceptibility of cells to DNA-damaging agents commonly used for cancer treatments. Recent studies have shown that manipulating the various players involved in regulating post-translational modifications to chromatin and exploiting differences in metabolism may prove to be effective methods for modifying cancer and normal cell sensitivity to damaging agents. In this review we discuss various ways of regulating chromatin structure and how these changes can influence cellular sensitivity to damage as well as the implications of these relationships for improving the efficacy and safety of cancer treatments.
Highlights
Epigenetics is the regulation of gene expression independent of the gene sequence itself via the interactions between DNA and proteins called histones [1]
When a cell is in S-phase of the cell cycle, its DNA must decondense and the nucleosome structures are reduced in order to open the DNA and allow the replication machinery to access the genes through tightly regulated processes [5, 12]; histones must be replicated and properly reoriented with accurate posttranslational modifications
Due to the unique metabolic state of cancer cells, they rely on specific epigenetic profiles that could be novel targets for treatments
Summary
Epigenetics is the regulation of gene expression independent of the gene sequence itself via the interactions between DNA and proteins called histones [1]. Various combinations of modifications to histones and DNA alter chromatin structure in order to regulate the global gene expression pattern in a cell and can vary based on cell type. There is often increased H4K5 acetylation and decreased H3K9 dimethylation to further open the chromatin structure at the site of Epigenetics and cellular sensitivity to DNA damage the lesion.
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