Review

www.cell-stress.com

Epigenetic mechanisms behind cellular sensitivity to

DNA damage
Amanda K. Williamson1, Zijing Zhu1 and Zhi-Min Yuan1,*
1
Department of Environmental Health, John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Bos-
ton, MA, USA.
* Corresponding Author:
Zhi-Min Yuan, MD, PhD, Director of John B. Little Center for Radiation Sciences, Department of Environmental Health, Harvard T.H.
Chan School of Public Health, 220 Longwood Avenue, Goldenson 544, Boston, MA, 02115, USA; Tel: 617-432-2139;
E-mail: [email protected]

ABSTRACT Epigenetic regulation of gene expression in cells is a complex and doi: 10.15698/cst2018.07.145
dynamic process that remains incompletely understood. The architecture of Received originally: 15.04.2018
in revised form: 17.05.2018,
the chromatin itself and its level of condensation can greatly impact the ex-
Accepted 18.05.2018,
pression of genes as well as the sensitivity of the DNA to damage. The com- Published 12.06.2018.
pact nature of heterochromatin typically results in gene silencing and re-
sistance to DNA-damaging agents, while less compact euchromatin results in
gene expression and increased sensitivity to injury. There are diverse ways in Keywords epigenetics, DNA damage,
which the chromatin structure, and therefore the sensitivity of cells to dam- cellular sensitivity, metabolism, cancer,
chromatin structure, therapeutics.
age, 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 Abbreviations:
cell cycle. When these processes are dysregulated, as in cancer cells, the ATM – Ataxia Telangiectasia Mutation,
chromatin structure is also altered, ultimately changing the gene expression DSB – double-stranded break,
profile as well as the susceptibility of cells to DNA-damaging agents common- HDAC – histone deacetylase,
HAT – histone acetyltransferase.
ly 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.

INTRODUCTION repair mechanisms [2, 3]. Thus, modulating the interac-

Epigenetics is the regulation of gene expression independ- tions between DNA and histones via post-translational
ent of the gene sequence itself via the interactions be- modifications represents a method of regulating gene ex-
tween DNA and proteins called histones [1]. In the nucleus, pression [1, 3].
DNA is highly compacted by wrapping around four major There are two major types of chromatin: heterochro-
histones, H2A, H2B, H3 and H4, to form chromatin. These matin, a transcriptionally inactive form in which DNA is
histones, bound to DNA, arrange into an octamer to create compacted, and euchromatin, a transcriptionally active
a nucleosome [1, 2]. The level of chromatin compaction form in which DNA is more relaxed [3]. Chromatin compac-
within these structures determines the accessibility of tion is regulated by post-translational modifications to his-
genes to cellular machinery necessary for their transcrip- tones and DNA, including methylation, acetylation, phos-
tion into mRNA that ultimately gets translated into pro- phorylation and ubiquitination. Methylation of DNA and
teins. The higher order chromatin structure also impacts histone tails is a hallmark of chromatin compaction, as
the degree of exposure of the DNA to damaging agents and heterochromatin is distinguished by tri-methylation on

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A.K. Williamson et al. (2018) Epigenetics and cellular sensitivity to DNA damage

lysine 27 of histone H3 (H3K27me) and di-/trimethylation the lesion. This extensive decompaction process and H4
on lysine 9 of histone H3 (H3K9me). However, methylation hyperacetylation triggers the accumulation and docking of
patterns are context-dependent, as trimethylation of lysine repair proteins at the site of the break, such as Ataxia Tel-
4 on H3 (H3K4me3) results in gene activation. Conversely, angiectasia Mutation (ATM). ATM plays a role in identifying
acetylation of basic lysine and arginine residues on his- the specific lesion and triggering its repair through various
tones reduces their positive charge, and therefore de- mechanisms including non-homologous end joining (NHEJ)
creases their binding affinity to the negatively charged and homologous recombination (HR) [5, 8]. However, het-
backbone of DNA, resulting in a more relaxed chromatin erochromatin is often seen as being refractory to DNA re-
state [4]. Euchromatin is characterized by hyperacetylation pair if damage does occur because of its condensed nature
of histones, including acetylation of histone H3 lysine 9 and preventing access to repair proteins. It has also been
H4 N-terminal lysines [3, 5]. shown to be more reliant upon ATM-induced chromatin
These post-translational modifications are heritable relaxation in order to effectively reduce the heterochro-
and used to control gene expression, as well as to protect matic structure to allow for repair [8], thus the specific
DNA from mutation. The higher order chromatin structure type of chromatin remodeling that occurs in response to
is extremely important for maintaining genome stability at DNA damage remains context-dependent [5]. Overall, epi-
key points in the genome [5]. For example, DNA is more genetic modifications to the chromatin architecture play a
highly methylated, and therefore compacted, in areas that major role in regulating the susceptibility of DNA to dam-
contain repetitive sequences to prevent the expression of age as well as the ability of the cell to repair that damage.
non-coding DNA, induction of double-stranded breaks
(DSBs), transposable elements and inappropriate recombi- THE INFLUENCE OF CELL METABOLISM ON CHROMATIN
nation events likely to occur at repetitive DNA sequences. STRUCTURE
These events can lead to mutations, genome instability and One way that chromatin state and cellular sensitivity to
cancer development [5, 6]. In this way, various combina- damage can be modulated is through the direct interplay
tions of modifications to histones and DNA alter chromatin between the chromatin architecture and the metabolic
structure in order to regulate the global gene expression state of a cell. Various enzymes play a role in the regulation
pattern in a cell and can vary based on cell type. Often of chromatin compaction, including DNA methyltransferas-
times, this precise chromatin architecture at specific gene es, such as EZH2, and histone deacetylases (HDACs). Me-
sequences, including the promoter regions of oncogenes thyltransferases are protein complexes with enzymatic
and tumor suppressors, is altered in cancer cells [6]. Chro- activity that catalyze the addition of methyl groups onto
matin compaction and relaxation is a dynamic and inte- arginine and lysine residues on histones. This methylation
grated process dependent upon many factors, including increases the binding affinity between the negatively
cell status and metabolism. In this context, regulation of charged backbone of DNA and the positive charge on the
DNA architecture may prove to be a novel method to alter histones, resulting in chromatin compaction and reduction
cells’ susceptibility to DNA-damaging agents used in cancer of gene transcription. Additionally, HDACs remove acetyl
therapies. groups, which are responsible for maintaining a more open
structure, further allowing the chromatin to become more
CHROMATIN STATUS IMPACTS CELLULAR SENSITIVITY compact [5].
TO DNA DAMAGE Many of the enzymes that alter chromatin structure
Chromatin that is more compact, as in heterochromatin, is are dependent upon cellular metabolites and nutrient ac-
more resistant to DNA damage and protected from DSBs, cessibility for their substrates and co-factors in order to
while chromatin that is less compact is more sensitive to catalyze enzymatic modifications to histones and DNA. This
damage [5, 7]. A recent study found that decondensed is one major way that chromatin dynamics respond to the
chromatin exhibited a 5-50-fold increase in radiation- environment and alter gene expression [5, 9]. For example,
induced double-stranded DNA breaks [7]. Heterochromatin histone methyltransferases catalyze the transfer of a me-
is refractory to DSBs because its compact nature limits DNA thyl group from S-adenosyl methionine, which is derived
exposure to damaging agents and surrounding non-histone from the essential amino acid methionine and must be
proteins in the nucleosome structure provide physical pro- obtained via the diet through folate, vitamin B and choline,
tection to the DNA [3, 5]. However, chromatin plasticity is because they all carry a methyl group [4, 9]. Deficiencies in
critical in order to repair DNA breaks induced by external vitamin B12 can result in DNA hypomethylation in the
stressors and varies based on the chromatin architecture. promoter regions of some genes and has been linked to an
When DNA damage occurs, the nucleosome structure be- increased risk of various cancers. A deficiency of methyl
comes disrupted and chromatin is decompacted through donor molecules has also been shown to impact DNA
various types of histone modifications, including destabili- methylation patterns and gene expression in fetal devel-
zation of the nucleosome by incorporation of the H2A.Z opment, demonstrating the impact of nutrient availability
histone to replace H2A, as well as ubiquitination and sub- and metabolism on epigenetic regulation of gene expres-
sequent removal of H3 and H4. Additionally, there is often sion [4].
increased H4K5 acetylation and decreased H3K9 dimethyl- Conversely, acetyl-CoA is a substrate of histone acetyl-
ation to further open the chromatin structure at the site of transferases (HATs) and is highly produced during aerobic

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A.K. Williamson et al. (2018) Epigenetics and cellular sensitivity to DNA damage

glycolysis, generating increasingly acetylated histones and be replicated and properly reoriented with accurate post-
less compact chromatin under this metabolic state [9]. translational modifications. If this order is not maintained,
Cancer cells are known to perform an increased rate of DNA can later undergo inappropriate transcription, leading
aerobic glycolysis, generating high levels of acetyl-CoA, as to the formation of DNA-RNA hybrids, R-loops and increas-
well as triggering the activation of AKT and MYC. This phe- ing the likelihood of DNA to be exposed to breaks [5]. Thus,
nomenon is known as the Warburg effect. The rise of these rapidly dividing cells are much more susceptible to DNA
metabolites and pathways increases the activity of HATs to breaks and the formation of improper chromatin struc-
acetylate histones, opening the DNA and promoting the tures, leading to the activation and/or silencing of incorrect
transcription of growth-related genes. This process links genes. In contrast, a non-dividing cell that is in the gap
changes in cellular metabolism to altered chromatin archi- phases of the cell cycle typically has more condensed DNA
tecture that ultimately results in the modified gene expres- and stable nucleosome presence [12]. As previously dis-
sion profiles in cancer cells [1, 9, 10]. cussed, this condensation protects the DNA from DSBs [7].
Additionally, histone demethylases including JMDH2 Due to the compact nature of heterochromatin in non-
and TET2 require α-ketoglutarate generated from the TCA dividing cells and tissues consisting of non-dividing cells,
cycle as a substrate, as well as oxygen and Fe (II), in order they are more resistant to DNA damage. Variations in the
to oxidize methylcytosines on histones to hydroxymethyl- metabolic programs and status of different cell types de-
cytosines and promote the removal of a methyl group [1, termine the level of chromatin compaction and exposure
9]. This mechanism is implicated during cell differentiation of DNA to replication errors, which determines the cells’
in order to activate differentiation-associated genes. Muta- genomic integrity and sensitivity to DNA damage. It is this
tions in this pathway can cause hypomethylation of these dynamic regulatory loop based upon cell cycle and me-
genes, preventing their transcription and resulting in a tabolism that is implicated in various epigenetic changes in
hyperproliferative phenotype characteristic of tumors [9]. cancer cells [6].
α-ketoglutarate is derived from both glucose and gluta- .
mine taken in by the cell for generation of ATP, thus fur- CANCER CELL METABOLISM INFLUENCES DNA
ther demonstrating the influence of the cellular metabolic ARCHITECTURE
profile and the availability of metabolites from the envi- Epigenetics has been shown to play a major role in the
ronment on the ability of enzymes to alter the chromatin initiation and propagation of cancer cells due to its influ-
status and regulate epigenetics [1, 9]. ence on the expression of oncogenic and tumor suppressor
Cell type and cell state, such as pluripotent versus dif- genes [6]. Cancer cells are characterized by rapid cell divi-
ferentiated or primary versus metastatic cancer cells, are sion and deregulated metabolic programs centered around
also directly related to chromatin design. The chromatin increasing the production of metabolites necessary for
modification profile of a cell determines its phenotypic rapid growth and division. This unique cancer cell metabol-
properties and the transition between cell states is de- ic profile impacts chromatin structure within the cell [10].
pendent upon changes to the epigenomic profile [6, 11]. Because of their rapidly-dividing nature, cancer cells typi-
Embryonic stem cells contain both activating and repres- cally have less compact DNA, leading to overall genomic
sive histone modifications at the site of promoters of genes instability and increased likelihood of chromosome rear-
specifically related to development. These modifications rangements. Additionally, their chromatin is characterized
can be altered in stem cells at different developmental by global hypomethylation and acetylation of histones in
stages to either induce or silence gene expression, whereas promoter regions of genes that regulate growth and trans-
differentiated cells have large areas of repressive H3Kme2 formation, resulting in upregulation of growth-promoting
to maintain the expression of genes in accordance with a and glycolytic genes [6, 10]. Cancer cells will also often
specific cell type [6]. Cellular metabolism greatly influences exhibit epigenetic silencing of tumor suppressor proteins,
the accessibility of components needed by enzymes to DNA repair genes and transcription factors due to hyper-
alter chromatin and thus determines whether a cell can methylation at the site of their promoters. These epigenet-
transition between these different states. For example, ic alterations to gene expression can result in rapid cell
reduced levels of NAD+ due to glycolysis decreases the ac- growth and therefore accumulation of many mutations
tivity of NAD+-dependent histone deacetylases, resulting in observed in cancer cells [6].
increased gene expression and a cancerous phenotype. Its Epigenetic regulators are also commonly dysregulated
availability is also associated with chromatin compaction in cancers. For example, EZH2 is frequently overexpressed
and gene silencing during the differentiation of mouse in breast and prostate cancers, causing increased H3K27
muscle stem cells [11]. methylation, chromatin compaction and transcriptional
Another determining factor of chromatin state is the repression of tumor suppressor genes. This variation in
cell cycle. Dividing cells rapidly replicate their DNA and cancer cells is one way in which deregulated epigenetic
chromatin configurations through a complex process of changes may contribute towards their malignant pheno-
chromatin remodeling. When a cell is in S-phase of the cell type [6].
cycle, its DNA must decondense and the nucleosome struc- Additionally, studies have shown that epigenetic altera-
tures are reduced in order to open the DNA and allow the tions observed in various cancers may be due to the initia-
replication machinery to access the genes through tightly tion of these changes in normal and progenitor cancer
regulated processes [5, 12]; however, histones must also

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A.K. Williamson et al. (2018) Epigenetics and cellular sensitivity to DNA damage

stem cells. Methylation of genes involved in regulating self- notion that p53 downregulation is necessary for prolifera-
renewal “gatekeeper” genes can allow progenitor cells to tion [16, 17]. Thus, our lab sought to identify an indirect
develop infinite self-renewal capacity and therefore be p53-mediated molecular mechanism behind the apparent
selected for survival and further replication, leading to sensitivity in renewable tissues to chemotherapeutic
accumulation of mutations and tumorigenesis. This epige- agents.
netic profile generates transformed stem-cell-like cancer Because these tissues expressed high levels of p53,
cells with a high rate of proliferation [6]. they also had high levels of its transcriptional target,
The frequently observed decondensation of chromatin MDM2. It had been previously determined that MDM2
in rapidly-dividing cancer cells may be a beneficial aspect physically associates with EZH2 [14]; therefore, our lab
to target for therapy. The less compact chromatin struc- explored this interaction further by demonstrating that
ture allows for increased exposure, and therefore suscep- MDM2, when in a complex with MDMX, acts as a novel E3-
tibility of the chromatin to DNA-damaging agents common- ligase for EZH2 and leads to its degradation. Because sensi-
ly used in cancer therapies. Because epigenetics can be tive tissues such as the spleen and thymus displayed an
modified and potentially reversed in order to manipulate increased turnover of EZH2, their chromatin was less com-
gene expression, it may prove to be advantageous to tar- pact and more susceptible to damage from chemotherapy
get epigenetic regulators in order to both alter the expres- and radiation. Conversely, when p53 was mutated and
sion of tumor-suppressor and oncogenic genes in cancer transcriptionally inactive in these tissues, MDM2 levels
cells as well as influence their vulnerability to DNA- were diminished, while EZH2 levels were increased in con-
damaging treatments [6]. Chromatin dynamics in general comitance with increased H3K27me3, chromatin compac-
are often dysregulated in various different ways in cancers tion, and protection against radio- and chemotherapy. Our
that, when combined with additional metabolic alterations novel findings for the role of EZH2 in tissue sensitivity
and genetic mutations, contribute to modifications in gene demonstrate a previously unrecognized mechanism and
expression. Thus, epigenetics is one major factor in a com- possible target for protecting and/or sensitizing tissues to
plex and often context-dependent network of elements cancer therapies by manipulating epigenetic modifiers [13].
that lead to a cancerous phenotype in cells. By targeting enzymes involved in chromatin structure
modification, the status of DNA in cancer cells and normal
CONCLUSION: IMPLICATIONS OF EPIGENETIC cells can be altered to regulate tissue sensitivity to treat-
REGULATION FOR IMPROVED CANCER TREATMENT ments. Targeting methyltransferases or deacetylases to
Exploiting chromatin architecture regulation in order to reduce their activity in cancer cells would make the DNA
manipulate cancer cell response to treatments is a thera- less compact and increase its susceptibility to damage.
peutic potential that requires further research. Due to the Additionally, maintaining chromatin compaction in normal
unique metabolic state of cancer cells, they rely on specific cells could protect them from DNA damage and unfavora-
epigenetic profiles that could be novel targets for treat- ble toxicity from chemotherapeutics. Combinational thera-
ments. Because compact chromatin in heterochromatin is pies that utilize inhibitors of overactive methyltransferases
less susceptible to DNA damage and more favorable for in cancer cells to open chromatin in conjunction with DNA-
survival [5], regulation of the chromatin architecture via damaging agents such as gamma-rays, heavy ions and
manipulation of enzymes involved in modifying histones chemicals could enhance cancer cell-killing. Conversely,
may be a useful strategy to increase cancer cell sensitivity stabilizing methyltransferases in normal cells to maintain
to DNA-damaging agents. DSBs in heterochromatin are less their chromatin compaction and genome integrity could
common because the DNA is compact and protected, but protect these cells from adverse side effects of using DNA-
they are also less likely to be repaired or undergo slow damaging agents to kill cancer cells. Overall, modulation of
repair and therefore prove to be more deleterious [3, 5]. epigenetic enzymes to alter chromatin structure in normal
Additionally, DSBs initiate decondensation of chromatin in and cancer cells represents a previously understudied ave-
order to allow for repair [5, 7], which would increase the nue of therapeutic potential for cancer treatments that
accessibility of chromatin to further damage. Therefore, may prove to be extremely beneficial in the future.
either reducing the compaction of chromatin to expose
more DNA to damage or targeting the damage effect to ACKNOWLEDGMENTS
heterochromatin in cancer cells could be a powerful way to This work was supported in part by the Morningside Founda-
increase cell death. tion, the Zhu Fund and grants from the National Cancer Insti-
Recently, our lab has demonstrated that the level of tute at the National Institute of Health (R01CA85679,
the DNA methyltransferase, EZH2, is a determinant of tis- R01CA167814, and R01CA125144).
sue sensitivity to chemotherapy and radiation due to the
level of p53 in renewable tissues [13]. EZH2 is the catalytic CONFLICT OF INTEREST
component of Polycomb Repressor Complex 2 (PRC2), The authors declare no conflict of interest.
which trimethylates histone 3 at lysine 27, condensing
chromatin and repressing many genes [14]. It has been COPYRIGHT
shown that sensitive tissues with high rates of replication © 2018 Williamson et al. This is an open-access article re-
often have high levels of p53 [15], which contradicts the leased under the terms of the Creative Commons Attribu-
tion (CC BY) license, which allows the unrestricted use,

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A.K. Williamson et al. (2018) Epigenetics and cellular sensitivity to DNA damage

distribution, and reproduction in any medium, provided Please cite this article as: Amanda K. Williamson, Zijing Zhu and
the original author and source are acknowledged. Zhi-Min Yuan (2018 Epigenetic mechanisms behind cellular sensi-
tivity to DNA damage. Cell Stress 2(7): 176-180. doi:
10.15698/cst2018.07.145

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