Resolving DNA Damage: Epigenetic Regulation of DNA Repair

Abstract

Epigenetic research has rapidly evolved into a dynamic field of genome biology. Chromatin regulation has been proved to be an essential aspect for all genomic processes, including DNA repair. Chromatin structure is modified by enzymes and factors that deposit, erase, and interact with epigenetic marks such as DNA and histone modifications, as well as by complexes that remodel nucleosomes. In this review we discuss recent advances on how the chromatin state is modulated during this multi-step process of damage recognition, signaling, and repair. Moreover, we examine how chromatin is regulated when different pathways of DNA repair are utilized. Furthermore, we review additional modes of regulation of DNA repair, such as through the role of global and localized chromatin states in maintaining expression of DNA repair genes, as well as through the activity of epigenetic enzymes on non-nucleosome substrates. Finally, we discuss current and future applications of the mechanistic interplays between chromatin regulation and DNA repair in the context cancer treatment.

Keywords: DNA damage; DNA repair; chromatin remodeling; epigenomics.

Figure 1

Early steps of DNA damage response that include DNA damage recognition and recruitment of additional repair factors in mismatch repair (MMR), nucleotide excision repair (NER), and base excision repair (BER) pathways.

Figure 2

Epigenetic-driven chromatin modifications and DNA repair (A) Epigenetic regulation of key DNA repair processes with emphasis in chromatin modifications. (B) Multilayer epigenetic regulation upon DNA damage response (DDR).

Figure 3

Regulation of key non-histone DDR components by epigenetic factors. (A) Direct lysine methylation of p53. (B) Indirect regulation of p53 through methylation by epigenetic factors. (C) Examples of non-histone epigenetic regulation of DDR components. Of note the opposing roles of SET9 and LSD1 on E2F1 methylation. (D) Regulation of Rb-E2F1 axis by epigenetic factors.

Figure 4

Targeting multiple steps of DNA damage resolution leads to efficient cell killing. Chromatin regulation is necessary for efficient DNA repair. These pathways are often defective in cancer (asterisks *) and can be targeted using specific inhibitors. As a result, synthetic lethal interactions can be exploited with multiple ways, which can be very advantageous in the clinical setting, where changes in treatment are required.