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Review
. 2021 Jul 7:8:685440.
doi: 10.3389/fmolb.2021.685440. eCollection 2021.

Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review

Alejandra Fernandez  1 , Connor O'Leary  1   2 , Kenneth J O'Byrne  1   2 , Joshua Burgess  1   2 , Derek J Richard  1   2 , Amila Suraweera  1   2
Affiliations
Review

Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review

Alejandra Fernandez et al. Front Mol Biosci. .

Abstract

Upon the induction of DNA damage, the chromatin structure unwinds to allow access to enzymes to catalyse the repair. The regulation of the winding and unwinding of chromatin occurs via epigenetic modifications, which can alter gene expression without changing the DNA sequence. Epigenetic mechanisms such as histone acetylation and DNA methylation are known to be reversible and have been indicated to play different roles in the repair of DNA. More importantly, the inhibition of such mechanisms has been reported to play a role in the repair of double strand breaks, the most detrimental type of DNA damage. This occurs by manipulating the chromatin structure and the expression of essential proteins that are critical for homologous recombination and non-homologous end joining repair pathways. Inhibitors of histone deacetylases and DNA methyltransferases have demonstrated efficacy in the clinic and represent a promising approach for cancer therapy. The aims of this review are to summarise the role of histone deacetylase and DNA methyltransferase inhibitors involved in DNA double strand break repair and explore their current and future independent use in combination with other DNA repair inhibitors or pre-existing therapies in the clinic.

Keywords: DNA double strand breaks; DNA methyltransferase inhibitors; DNA repair; epigenetic mechanisms; histone deacetylase inhibitors.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
DNA Lesions and Repair Pathways. Schematic representation of DNA damage and repair. Exogenous and endogenous agents induce DSBs, which are repaired by the HR or NHEJ pathways.
FIGURE 2
FIGURE 2
DNA double strand break repair pathways. (A) HR fixes two-ended DSBs by a resection process. A recombinase will then induce strand invasion. The single strand is then extended, using the complementary strand as template. Recapture of the second end occurs followed by ligation. The main proteins involved in this pathway are hSSB1, MRN complex, RPA, BRACA1/2 and Rad51. (B) NHEJ of DSBs in DNA is accomplished by a series of proteins that work together to carry out the synapsis, preparation, and ligation of the broken DNA ends. The main proteins involved in NHEJ eukaryotes are Ku and DNA-PK complexes, XLF and the XRCC4/DNA ligase IV complex.
FIGURE 3
FIGURE 3
Epigenetic Mechanisms - Histone Modifications and DNA methylation. (A) A schematic representation of the covalent post-translational modifications to histone proteins. These include ADP-ribosylation, ubiquitination, sumoylation, methylation, acetylation, and phosphorylation. (B) A schematic representation of the DNA methylation process that occurs by addition of the methyl (CH3) group to the DNA, thereby often modifying the function of certain genes and affecting gene expression.
FIGURE 4
FIGURE 4
Histone Acetylation and DNA methylation. (A) This figure shows the acetylation mechanism of adding an acetyl coenzyme A (acetyl CoA) to the N-terminal tail of a histone through the HAT enzyme, leading to a relaxed chromatin. Conversely, histone deacetylation removes the acetyl CoA through the HDAC enzyme, leading to a condensed chromatin and transcriptional repression. When a HDACi is added the acetyl CoA group cannot be removed and therefore, the chromatin remains relaxed and transcription remains active. (B) This figure depicts DNA methylation process being blocked by a DNMTI. The inhibitor prevents the addition of the methyl group to the CpG island site in DNA, inhibiting transcriptional repression.
See this image and copyright information in PMC

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