Mutation Research 750 (2013) 23–30

Contents lists available at ScienceDirect

Mutation Research/Fundamental and Molecular
Mechanisms of Mutagenesis
journal homepage: www.elsevier.com/locate/molmut
Community address: www.elsevier.com/locate/mutres

Review

Mammalian DNA repair: HATs and HDACs make their mark through
histone acetylation
Fade Gong, Kyle M. Miller ∗
Section of Molecular Genetics and Microbiology, Institute for Molecular and Cellular Biology, University of Texas at Austin, 2506 Speedway Stop A5000,
Austin, TX 78712, USA

a r t i c l e i n f o a b s t r a c t

Article history: Genetic information is recorded in specific DNA sequences that must be protected to preserve normal
Received 30 April 2013 cellular function. Genome maintenance pathways have evolved to sense and repair DNA damage. Impor-
Received in revised form 3 July 2013 tantly, deleterious mutations that occur from mis-repaired lesions can lead to diseases such as cancer. As
Accepted 9 July 2013
eukaryotic DNA is bound by histone proteins and organized into chromatin, the true in vivo substrate of
Available online 6 August 2013
transcription, replication and DNA repair is chromatin. Almost 50 years ago, it was found that histones
contained the post-translational modification (PTM), acetylation. With the cloning and identification of
Keywords:
transcription associated histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes that
Chromatin
DNA repair write and erase the histone acetylation mark respectively, it was realized that this histone modification
DNA damage response could be dynamically regulated. Chromatin is subjected to numerous PTMs that regulate chromatin struc-
Genome stability ture and function, including DNA repair. As different organisms contain different histone modifications,
Histone acetylation chromatin-associated proteins and chromatin states, it is likely that chromatin-templated processes such
as DNA repair will exhibit organismal differences. This article focuses on the DNA damage response (DDR)
in mammalian cells and how the concerted activities of HAT and HDAC enzymes, and their histone acety-
lation targets, specifically participate in DNA double-strand break (DSB) repair. Defects in DNA repair and
chromatin pathways are observed in cancer, and these pathways represent cancer therapeutic targets.
Therefore, understanding the relationship between DNA repair and histone acetylations is important for
providing mechanistic details of DSB repair within chromatin that has the potential to be exploited in
the clinic.
© 2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
1.1. DNA damage response (DDR) in mammalian cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
1.2. Chromatin regulation by histone modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
1.3. Regulation of histone acetylation by HATs and HDACs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2. Histone acetylation and DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3. Histone acetylation and DNA double-strand break repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.1. Histone variant H2AX and histone H2A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.2. Histone H4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.3. Histone H3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
4. Additional histone acetylations and DDR pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

∗ Corresponding author. Tel.: +1 5124715045.

E-mail address: kyle.miller@austin.utexas.edu (K.M. Miller).

0027-5107/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.mrfmmm.2013.07.002
24 F. Gong, K.M. Miller / Mutation Research 750 (2013) 23–30
1. Introduction
1.1. DNA damage response (DDR) in mammalian cells
The nuclear milieu is a harsh environment for our genetic infor-
mation since high incidences of DNA damage occur every day
within our cells [1,2]. Whether it be replication-dependent DNA
mismatches, transcriptional damage, the production of metabolic
by-products, exposure to exogenous DNA damaging agents or
therapeutic radiotherapy, these processes can all create damaged
DNA that must be faithfully repaired to maintain genome fidelity.
Eukaryotic cells respond to these genetic assaults by activating a
set of pathways termed the DNA damage response (DDR) [1,2].
The DDR represents a complex network of cellular pathways that
function to detect the damaged lesion in DNA, signal the presence
of the lesion to the cell to activate the appropriate response, and
ultimately to repair the lesion to maintain the correct sequence
of the DNA [1,2]. One particularly dangerous type of lesion is the
DNA double-strand break (DSB). A DSB makes a discontinuous DNA
molecule creating a precarious situation as unprotected DNA ends
can be acted upon by nucleases leading to degradation and/or inap-
propriately religated to other free ends resulting in a loss of genetic
information, chromosomal translocations or complete chromo-
some loss. Due to these particularly deleterious outcomes, DSBs
constitute the most cytotoxic class of all DNA lesions. In mammalian
cells, DSBs are repaired mainly by either homologous recombina-
tion (HR) or non-homologous end-joining (NHEJ) [3]. HR requires
the processing of DNA ends and a template for the accurate repair
of a DSB while NHEJ ligates the free DNA ends with little to no
processing of the DNA ends prior to ligation. It is important to note
that in mammalian cells, NHEJ is the main DSB repair pathway in
G1, and is also active in the G2 phase of the cell cycle [4,5]. For this
reason, the choice between HR and NHEJ has been an important and
active area of research in the field [6]. As DSB repair occurs within
the context of chromatin and many chromatin modifying enzymes
have been linked with DSB repair, the understanding of the rela-
tionship between DNA repair and chromatin is fundamental for
revealing the mechanistic details of how DNA repair pathways are
regulated to promote stability of the entire eukaryotic genome [7].
Yeast has provided important insights into the role of histone acety-
lation in genome stability and DNA repair [8–11]. Here, we focus
on our current understanding of the function and regulation of his-
tone acetylation in the DNA damage response (DDR) in mammalian
cells. Specifically, we aim to review how HAT and HDAC enzymes,
and their histone acetylation targets, participate in DNA double-
strand break (DSB) repair. Researchers are actively pursuing both
chromatin factors and DDR proteins as potential therapeutic tar-
gets for diseases, including cancer, so understanding the interplay
between chromatin and the DDR could reveal novel therapeutic
opportunities.
1.2. Chromatin regulation by histone modifications
Duplexed DNA in the nucleus of eukaryotic cells is largely com-
pacted into chromatin. The fundamental unit of chromatin is the
nucleosome [12], which consists of positively charged histone pro-
teins and negatively charged DNA [13]. Specifically, the nucleosome
consists of two copies each of the four core histones, H2A, H2B,
H3 and H4, as well as ∼146 bp of DNA wrapped nearly two times
around the histone octamer. Eukaryotic cells also contain linker his-
tones, histone 1 (H1), that bind linker DNA between nucleosomes
as well as binding surfaces within the nucleosome themselves
to promote chromatin compaction. Eukaryotic genomes contain
multiple chromatin states that change depending on cell type and
cell-cycle phase as well as the processes that act upon a particular
region of the genome at any given time. For example, active
transcription correlates with an “open” chromatin configuration
(i.e. euchromatin) while transcriptionally repressed regions results
in a more “closed” chromatin state (i.e. heterochromatin). Chro-
matin remodeling activities including nucleosome repositioning,
histone eviction/deposition, and histone variant incorporation
can regulate chromatin. Another mechanism that regulates chro-
matin states is the post-translational modifications (PTMs) that
decorate histones. Histones are modified on distinct amino acid
residues with a vast array of different PTMs including phosphory-
lation, methylation, ubiquitylation, sumoylation and acetylation,
including several that are involved in DSB repair [14–17].
Histone modifications can affect chromatin structure in multi-
ple ways. The basic charge of histones is due to the high proportion
of positively charged lysine and arginine residues that are found
in all histone proteins. Negatively charged DNA interacts electro-
statically to regions of the histone that contain these amino acids.
Modifications of either lysines or arginines have the potential to
disrupt DNA/protein and protein/protein interactions by changing
the charge of the modified amino acid [14,18]. Histone marks can
also act as high affinity binding sites for proteins that contain bind-
ing domains that recognize histone PTMs. Histone binding domains
exists for many PTMs including phosphorylation, methylation and
acetylation. For example, twin-BRCT domains can bind phospho-
rylated histones, chromodomains can exhibit binding preferences
for methylated lysines and bromodomains can specifically interact
with acetylated lysine residues [14,18,19]. As an example, meth-
ylation of lysine 9 of histone H3 provides an interaction motif for
the chromodomains of HP1 proteins, which facilitate the formation
of heterochromatin and gene repression [20,21]. Trimethylation
of lysine 4 of histone H3 creates a binding site for transcriptional
complexes, leading to gene activation and euchromatin formation.
Thus, different chromatin states and functions found throughout
the genome can be regulated and established by the modification
of context specific amino acid residues on histones.
1.3. Regulation of histone acetylation by HATs and HDACs
Acetylation of histones was one of the first PTMs identified [22]
and represents the addition of an acetyl group ( COCH3 ) onto the
␧-amino group of lysines (Fig. 1). This is not the only modification
that occurs on lysines as other PTMs including methylation,
ubiquitylation, sumoylation, biotinylation and succinylation have
been identified, making lysines one of the most diversely modified
amino acids [14,23]. Histone acetylation is regulated by histone
acetyltransferases (HATs) and histone deacetylases (HDACs) that
catalyze the addition and removal, respectively, of the acetyl
moiety from lysines (Fig. 1). From the initial discovery of the first
HAT and HDAC involved in gene activation, it became apparent
that histone acetylation was a regulatable phenomenon that par-
ticipated in site-specific processes such as transcription [24,25].
Mammalian cells contain at least 17 HATs and 18 HDACs (Table 1).
HATs are diverse and fall into several families including GNAT (ex.
GCN5), MYST (ex. TIP60) and the “orphan” family (ex. p300) [26].
Both GCN5 and p300 contain bromodomains, and TIP60 exists in
the p400-Tip60/NuA4 complex that comprises a bromodomain
containing protein, which reinforces the notion of how histone
acetylation regulates the specificity, targeting and activity of these
enzymes [27,28]. Mammalian HDACs fall into 4 classes (Table 1)
[29]. Class I HDACs (HDAC 1-3, 8) are nuclear and ubiquitously
expressed in all cells. Class II HDACs (HDAC 4-7, 9 and 10) are
cell-type specific and are expressed mostly in the cytoplasm but
can become nuclear upon various stimuli. Class III HDACs are
the NAD-dependent Sirtuins (SIRT1-7) where SIRT1, 6 and 7 are
nuclear, SIRT2 is mainly cytoplasmic and SIRT 3-5 are mitochon-
drial [30]. Class IV contains only one member, HDAC11, which is
mainly expressed in the nucleus in a cell-type specific manner.
 F. Gong, K.M. Miller / Mutation Research 750 (2013) 23–30
+
NH 3
CH 2
CH
CH 2
CH
CH 2
CH
CH 2
CH
CH
Lys
HAT
HDAC
Fig. 1. Lysine acetylation. The addition of an acetyl (Ac) moiety on the ␧-amino group of a lysine residue is catalyzed by histone acetyltransferases (HATs) and this reaction
is reversed by histone deacetylases (HDACs). Acetyl-lysine readers are comprised mainly of proteins containing a bromodomain but other acetyl-lysine binding domains
(indicated) have been reported [98].
Collectively, many of these enzymes have been shown to function in
the DNA damage response by targeting specific histone acetylation
sites (Table 1 and Fig. 2A). These enzymes also target non-histone
substrates, for example ATM [31] and p53 [32], that are critical for
the DDR, although this review will focus mainly on their histone
targets.
2. Histone acetylation and DNA damage
Histone acetylation was first linked with a DNA damage
response in human cells when it was observed that histones
are rapidly acetylated after exposure to ultraviolet radiation (UV)
[33]. Interestingly, hyperacetylation of histones is rapidly followed
by hypoacetylation and this response is sensitive to UV dose
as low doses promoted more hyperacetylation and high doses
resulted in hypoacetylation. Repair of UV lesions occurs more
rapidly in hyperacetylated histones, which led to the idea that
chromatin accessibility occurring after histone acetylation would
allow repair proteins to gain access to the damaged lesion [34].
These data led to the “access-repair-restore” model whereby chro-
matin would be altered to allow access and repair of lesions
followed by a restoration of chromatin organization [35]. Sub-
sequent work has given more molecular details of the enzymes
and histone acetylation sites involved in this process. GCN5-
dependent H3K9 acetylation, and H4K16Ac, are rapidly induced
following UV damage [36]. Global hypoacetylation of H3K9 and
H3K56 is observed after high doses of UV as well [37,38]. These
histone acetylation changes potentially regulate chromatin orga-
nization following UV damage. Defining how global changes in
histone acetylation upon UV damage regulates chromatin struc-
ture, nuclear processes, such as transcription, as well as the repair
of the UV lesion will require further analysis in mammalian cells.
Regardless, the “access-repair-restore” model has been applied to
DSB repair in mammalian cells where it is believed that a con-
certed effort from chromatin modifying enzymes, such as HATs
and HDACs, as well as chromatin remodeling complexes, histone
variants and histone chaperones collectively regulate chromatin
organization to promote DSB repair by HR and NHEJ pathways
(Fig. 2A) [7].
3. Histone acetylation and DNA double-strand break repair
Core histones and histone variants are modified by acetylation
and several sites have been shown to be involved in DSB repair
(Table 1).
25
Ac-Lys Readers
H O
Bromodomain
εN C CH 3
Double Bromodomain
CH 2
CH
Double PHD finger
CH 2
CH
Double PH domain
CH 2
CH
CH 2
CH
CH
Ac-Lys
3.1. Histone variant H2AX and histone H2A
Upon formation of a DSB in mammalian cells, one of the very
first chromatin events that occurs is the phosphorylation of the
histone variant H2AX on S139 to form ␥H2AX [39]. ␥H2AX is crit-
ical for many aspects of the DDR, including the maintenance of
genome integrity. This histone modification marks DSBs and is used
as a biomarker of DNA damage in cancer cells, making ␥H2AX the
most well-studied histone modification involved in the DDR [40].
However, acetylation of several lysines in H2AX have also been
described to impact DSB repair [17]. Upon DNA damage, the HAT
TIP60 acetylates H2AX on lysine 5 [28]. SIRT1 regulates TIP60 activ-
ity and depletion of SIRT1 results in H2AX K5Ac hyperacetylation
resulting in defective DDR activation at DSBs [41]. H2AX K5Ac also
regulates H2AX ubiquitylation after DSB formation, which affects
the dynamics of H2AX at break sites. H2AX lysine 36 acetylation
has also been identified [42,43]. This site is hyperacetylated by
the overexpression of the HATs, p300 or CBP [42]. H2AX−/− mouse
cells reconstituted with an unmodifiable H2AX at lysine 36 results
in defective IR-resistance while an unmodifiable H2AX at lysine
5 does not [42,43]. For H2AX acetylation, several important ques-
tions remain. The core histone H2A also contains K5 and K36 so it is
unclear whether the acetylation of these residues is H2AX-specific
in regards to DSB repair. In addition, no HDAC has been reported
for H2AX K36Ac and whether the function of H2AX acetylations
involves changes in chromatin structure and/or the involvement
of a histone acetylation binding protein is yet to be determined.
H2A has several additional acetylation sites and both H2AZ and
H2B have many acetylated lysines but the potential role of these
acetylation sites in DSB repair in mammalian cells awaits further
characterization [44].
3.2. Histone H4
Histone H3 and H4 bind as a tetramer in the nucleosome and
several acetylation sites on H4 are involved in the cellular response
to DNA damage. Early experiments identified the human HAT TIP60
as an important factor involved in the DDR [45]. TIP60 acetylates
both H3 and H4, as well as H2A, in vitro and mutating the acetyl-
transferase activity of TIP60 rendered cells defective in repairing
DSBs following IR suggesting that acetylation was critical for DSB
repair [45]. The first histone acetylation sites identified as targets
of the DDR in mammalian cells were on H4. Human MOF acetylates
H4K16Ac after IR exposure. Interestingly, this HAT also interacts
with ATM and reduction of MOF results in defective ATM activation
and DSB repair [46]. TIP60 functions in the p400-Tip60/NuA4 com-
plex to acetylate histones to promote remodeling of chromatin at
26 F. Gong, K.M. Miller / Mutation Research 750 (2013) 23–30

DSB
A
HATs/
HDACs HATs
HDACs

DSB repair

Repaired
DNA break
HATs/HDACs, Chromatin Remodeling complexes
Histone chaperones, Proteases

Chromatin
Restoration

acetylated &
Histones: deacetylated acetylated
deacetylated

53BP1
B 53BP1 BRCA1
Me2
HAT Ac Me2
K16 BRCA1
K20 (TIP60) K16 K20
H4 H4

HDAC
(HDAC1/2)

NHEJ HR

Fig. 2. Histone acetylation and DSB repair. (A) DSBs occur within a pre-existing chromatin acetylation landscape. HATs and HDACs, individually or in concert, are recruited to
the DSB site where deacetyation, acetylation or both activities occur on specific histone residues to create a repair proficient chromatin state that will promote either NHEJ or
HR. Restoration of chromatin to its pre-damaged state can occur through modification of existing chromatin or de novo chromatin assembly by the action of several distinct
chromatin modifying enzymes, histone chaperones and/or chromatin remodeling complexes. These activities, with or without HDACs and HATs, can also act upstream of
chromatin restoration at the level of detection and repair of DSBs. (B) Regulation of DSB repair pathway choice by histone acetylation.
Adapted from model presented in Tang et al. [56]. See text for details.

DSBs [28,47–50]. TIP60 activity is stimulated by H3K9me3 resulting
in acetylation of ATM to promote its activity [49]. The interaction
between TIP60 and ATM is regulated by TIP60 phosphorylation by
c-Abl, which is critical for the ability of ATM to sense chromatin
alterations, perhaps caused by aberrant histone acetylation, even
without the presence of damaged DNA [51]. Using an I-SceI (site-
specific homing endonuclease) single DSB system in mouse ES cells,
DSB induction induces the hyperacetylation of H4 0.5KB from the
DSB as determined by an antibody raised against H4 acetylated
at K5, K8, K12, K16 [48]. These acetylations were dependent on
the Trrap-TIP60 complex. Trrap-TIP60 is required for efficient HR
and this defect could be suppressed by the HDAC inhibitor sodium
butyrate, although the HDAC(s) were not identified. In another
study, using a DSB system with two I-SceI sites that could monitor
NHEJ specifically, H4 tetra acetylation on K5, K8, K12, and K16 was
shown to increase near a DSB [52]. However, these DSB-induced
acetylations were dependent on either p300 or CBP as depletion
of either of these HATs resulted in a defect in H4 Ac and H3K18Ac
inductions at a DSB. p300 and CBP, as well as TIP60, were shown to
decrease efficient NHEJ using this reporter system. ChIP analysis of
these histone marks adjacent to the DSB was performed in a region
that was transcriptionally silent in undamaged conditions but
became transcriptionally active after repair [52]. However, histone
acetylations are also associated with active transcription, which
could also affect the levels of these marks in these types of assays. In
addition, these systems rely on persistent DSBs. How these results
from persistent single-locus DSB systems relate to endogenous and
exogenous DSB formation that are occurring throughout the chro-
matin landscape from normal cellular processes or upon treatment
with DNA damaging agents, requires additional studies.
 F. Gong, K.M. Miller / Mutation Research 750 (2013) 23–30 27

Table 1
Histone acetylation sites and enzymes involved in the DDR in mammalian cells.

Name Localization DDR histone sites DDR pathways Recruitment

Mammalian histone acetyltransferases (HATs)

KAT1 HAT1 N, C n.d. DDR [80] n.d.
KAT2A GCN5 N H3K9/K14/K18/K23/56 DDR [37,62]; NER [36] UV [36]
[36,37,62]; H4K16 [36]
KAT2B PCAF N H3K9, H3K14 [81] DDR [81] n.d.
KAT3A CBP N H3K56 [60]; H3K18, NHEJ [52]; NER [82] Laser damage [52]
H4K5/K8/K12/K16
[52]; H2AXK36 [42]
KAT3B p300 N H3K56 [37,60,83]; NHEJ [52]; DDR [84,85]; NER [82] Laser damage [52]; UV [86]
H3K18,
H4K5/K8/K12/K16
[52]; H2AXK36 [42]
KAT4 TAF1 N n.d. DDR [87]
KAT5 TIP60 N H2AXK5 [28]; H4K16 HR [48,56,57]; DDR [45,88] IR [88]; R.E. [48,56]
[56,57]
KAT8 MOF N H4K16[46,53,89] DDR[46,53]; NHEJ & HR [89] n.d.
KAT13D CLOCK N, C n.d. DDR [90] Laser damage [90]
Other HATs: MOZ (KAT6A), MORF (KAT6B), HBO1 (KAT7), ELP3 (KAT9), TFIIIC90 (KAT12), SRC1 (KAT13A), ACTR (KAT13B), p160 (KAT13C)

Mammalian histone deacetylases (HDACs)

Class I HDAC1 N H3K56, H4K16 [54] NHEJ [54] Laser damage [54]
HDAC2 N H3K56, H4K16 [54] NHEJ [54] Laser damage [54]
HDAC3 N H3K9/K14, H4K5/K12 DDR [65] n.d.
[65]

Class II HDAC4 N n.d. DDR [91,92] IR [91]

HDAC9 N n.d. HR [93] n.d.
HDAC10 N,C n.d. HR [93] n.d.

Class III SIRT1 N H1K26 [66], H2AXK5 DDR [41,60,94,95]; HR [66] R.E. [66,94]
[41], H3K56 [60],
H4K16 [94]
SIRT2 C H3K56 [60] DDR [60] n.d.
SIRT6 N H3K9 [61] NHEJ [61]; HR [96]; BER [97] Laser damage [96]; R.E. [61]
Other HDACs: HDAC8 (Class I); HDAC5, HDAC6, HDAC7 (Class II); SIRT3, SIRT4, SIRT5, SIRT7 (Class III); HADC11 (Class IV)

Histone acetylation sites and enzymes involved in the DDR in mammalian cells. All mammalian HATs and HDACs are indicated. DNA damage affects on specific lysine sites, DDR
pathways and localization are provided for each enzyme. HATs and HDACs where a role in the DDR has not been reported are listed in the last line. Abbreviations: N-nuclear,
C-cytoplasmic, M-mitochondrial, n.d.-not determined, DDR-DNA damage response, NER-Nucleotide excision repair, NHEJ-Non homologous end-joining, HR-Homologous
recombination, BER-Base excision repair, UV-ultraviolet radiation, IR-Ionizing radiation, R.E.-restriction enzyme.

Of the potential H4 acetylation sites, H4K16Ac levels increase
after DNA damage and this site appears to play a critical role in
DSB repair [46,53,54]. After laser-induced DNA damage, H4K16Ac
levels decrease rapidly followed by a phase of acetylation result-
ing in increased levels at DNA damage sites [54]. The behavior of
H4K16Ac upon DNA damage mirrors those of DSB repair in human
cells. Indeed, repair of DSB by NHEJ occurs rapidly while HR repair
is much slower. Interestingly, HDAC1 and HDAC2 localize to laser-
induced damage rapidly, at a time where H4K16 deacetylation is
observed [54]. Depletion of both HDAC1 and HDAC2 results in
hyper-acetylation of H4K16Ac and defects in NHEJ in cancer cell
lines and genome instability in mice [54,55]. A molecular explana-
tion for some of these results has recently been provided. Using a
single locus DSB reporter system in human cells, TIP60 promoted
the accumulation of BRCA1 while inhibiting 53BP1 recruitment to
DSBs [56]. HDAC inhibitors, as well as depletion of both HDAC1 and
HDAC2, resulted in 53BP1 inhibition and accumulation of BRCA1 at
DSBs. Thus, the balance between BRCA1, which is involved in HR,
and 53BP1, which is involved in NHEJ, at DSBs is regulated by acety-
lation and deacetylation [56,57]. Using peptides containing specific
histone marks as well as NMR structural studies, acetylation of
H4K16 was found to be inhibitory toward the binding of the tudor
domains of 53BP1 to H4K20me2 [56]. Thus, regulation of H4K16Ac
can contribute to DSB repair pathway choice at DSBs by modulat-
ing the association of both 53BP1 and BRCA1 to promote NHEJ and
HR respectively (Fig. 2B). Of note, H4K16Ac also inhibits both intra-
and inter-nucleosomal folding to impede higher order chromatin
structure formation [58] and H4K16Ac could also affect interactions
of acetyl binding proteins with chromatin at DSBs. Thus, H4K16Ac
creates a steric hindrance to regulate protein binding at DSBs but
could also regulate repair through both chromatin structure and
direct histone binding of an acetyl-lysine reader. Multiple HATs,
including MOF and TIP60, have been reported to induce H4 acetyla-
tions upon DNA damage (Table 1). Defective chromatin remodeling
mediated by H4 acetylations in TIP60 or MOF deficient cells could
help explain their observed defects in DSB repair. How coordinated
HAT activities regulate these H4 sites to promote DSB repair by both
NHEJ and HR is unclear. H4 HATs could potentially target a subset
of histones at both damaged and undamaged sites to promote DDR
processes, including DNA repair and/or transcriptional regulation.
Increases in histone acetylations can also result from the inhibition
of HDACs, which could also be controlled by HAT activities on both
histone and non-histone targets.
3.3. Histone H3
Several acetylations on histone H3 are regulated by DNA
damage. Upon DSB induction, global levels of H3K9Ac, H3K56Ac
and H3K14Ac levels are regulated by the DDR [37,54,59–61].
The coordinated potential functions, for example transcription,
replication, chromatin structure and/or chromatin organization,
of these global changes in H3 acetylation are not yet fully under-
stood. For H3K14Ac, the nucleosomal binding protein HMGN1
was found to be required for H3K14Ac upon IR treatment [59].
Loss of HMGN1 resulted in defective ATM signaling suggesting
an additional link between histone acetylation and chromatin for
ATM activation. Several studies analyzed H3 acetylations specif-
ically at DSBs and found similar, as well as additional, alterations
28 F. Gong, K.M. Miller / Mutation Research 750 (2013) 23–30
in histone acetylation levels. Purification of damaged ␥H2AX
containing chromatin revealed higher levels of H3K9, K14, K18 and
K23 acetylation levels compared to chromatin that contained an
unphosphorylatable form of H2AX (S139A) [62]. These N-terminal
acetylations on H3 are dependent on GCN5 and were shown to
recruit the SWI/SNF chromatin remodeling complex to ␥H2AX
nucleosomes. Interestingly, the SWI/SNF complex includes BRG1,
a bromodomain-containing protein, which is recruited specifi-
cally to damaged chromatin through a bromodomain-dependent
interaction with H3K14Ac. Mutation of the bromodomain in BRG1
also resulted in sensitivity to IR suggesting that repair of DSBs
requires the binding of SWI/SNF to acetylated histones [62]. This
study shows that histone acetylations can modulate the DDR by
directly affecting the binding of factors through lysine acetylation
interactions at DSBs. Using site-specific restriction enzyme based
systems, H3K18Ac levels are increased while H3K56Ac levels are
reduced at DSBs [52,54]. HDAC1 and HDAC2 are recruited to sites
of damage where they regulate H3K56Ac levels and deacetylate
H3K56Ac to promote NHEJ [54]. p300/CBP acetylates H3K18,
which facilitates SWI/SNF chromatin remodeling activity at DSBs.
The activity of SWI/SNF is required for the efficient recruitment of
NHEJ factors, including KU, and inhibition of this pathway results
in defective NHEJ [52]. Collectively, certain histone acetylations on
H3 are regulated upon DNA damage and function to promote DSB
repair. H3 acetylations appear to not only regulate the recruitment
of DDR factors to sites of damage but also to promote nucleosome
and chromatin alterations at DSBs, as well as throughout the
genome. These activities clearly contribute to the DDR and to DSB
repair although the mechanistic details are still emerging.
4. Additional histone acetylations and DDR pathways
Although this review has focused on histone acetylations that
occur upon DSB formation, several other DNA damage pathways
also result in changes to acetylations on histones. DNA damage
occurring during replication is a major cause of endogenous DNA
damage and threatens both genetic and epigenetic integrity. His-
tone acetylations are involved in both genome maintenance during
replication as well as promoting the stability of the epigenome
[63]. Analysis of histone acetylations and the enzymes that regulate
them at active, stalled or collapsed replication forks has now been
made possible by a powerful technique called iPOND [64]. Using
this method, HDAC1, HDAC2 and HDAC3 were enriched at active
replication forks, and deacetylation of H4K5Ac and H4K12Ac, marks
required for chromatin maturation during S-phase, was observed.
Interestingly, deletion of HDAC3 in mouse cells results in the hyper-
acetylation of both of these histone marks, as well as H3K9Ac
and H3K14Ac, in S-phase [65]. HDAC3 null cells exhibit defects in
heterochromatin formation as well as increased genome instability
and defects in DNA repair [65]. Thus, these examples highlight the
importance of regulated histone acetylations by HATs and HDACs
during DNA replication and further work is required to detail the
precise regulation of these pathways in preventing epigenetic and
genome instability during replication. Histone acetylations are also
affected by oxidative stress. Indeed, SIRT1 binding to chromatin
is reduced upon oxidative stress resulting in increased histone
H1K26Ac [66]. SIRT1 is recruited to sites of DNA damage and is
required for DSB repair and genome stability [66]. As oxidative
stress, DNA damage and SIRT1 are implicated in aging in mam-
mals, histone acetylation is likely to also be involved in aging, as
has been shown in yeast for H4K16Ac [67]. Replicative aging of pri-
mary human cells also results in changes in histone acetylations at
both telomeres and throughout the genome [68]. Collectively, these
studies highlight a variety of biological processes that rely on his-
tone acetylation regulation. Additional roles for HATs and HDACs,
as well as specific histone acetylations, in nearly all aspects of the
DDR, as well as other cellular stresses such as aging, are sure to be
discovered.
5. Summary
Histone acetylations are determinant marks for both chromatin
structure and chromatin binding proteins. Regulation of these chro-
matin states by the concerted action of both HATs and HDACs
are critical for orchestrating the DDR in mammalian cells and
for promoting DSB repair. Several HATs and HDACs are recruited
to sites of DNA damage and several histone acetylation sites are
affected by DNA damage (Table 1). Thus, it is clear that HATs and
HDACs modulate chromatin surrounding a break to promote its
repair (Fig. 2A). Upon DSB formation, we envision that the pre-
damaged chromatin acetylation state will be regulated by specific
HDACs or HATs, as well as potentially a combination of both, to
create repair-proficient chromatin. This is reminiscent of transcrip-
tion where rapid acetylation followed by deacetylation by HATs
and HDACs respectively occurs to regulate chromatin dynamics
required for gene activation [69,70]. At a DSB, once repair is com-
plete, restoration of the damage-modified chromatin can occur
through the concerted activities of HDACs and/or HATs. De novo
chromatin assembly can also restore chromatin using the activities
of chromatin remodeling complexes and histone chaperones. His-
tone degradation following DNA damage has recently been shown
to occur in mammalian cells through a non-ubiquitin mechanism
that requires the proteosome activator PA200 [71]. Interestingly,
PA200 contains a bromodomain-like region that binds acetylated
histones to catalyze their degradation. These activities can also
act upstream of chromatin restoration for DSB repair, as has been
demonstrated for chromatin remodeling complexes. Thus, several
potential pathways exist, either through modifying the existing
chromatin or through de novo chromatin assembly at the site of a
DSB that have the potential to restore chromatin to its pre-damaged
state.
A comprehensive view of how and why specific histone acety-
lations are regulated by DNA damage globally, as well as at DSBs,
is lacking in mammalian cells. What the DNA damage-dependent
functions of each individual histone acetylation are at each genome
location, for a given cellular response and repair pathway, remains
unclear. The variability of chromatin states within cell-cycle phases,
cell types and physiological conditions compounds the ability to
provide an all-inclusive model of DSB repair and histone acetyla-
tions. Rather, like transcription, histone acetylations are likely to
regulate DSB repair in a site-specific context that depends on multi-
ple factors including, but not limited to, existing chromatin modifi-
cations, chromatin structure, cell cycle phase, genome location and
DSB repair pathway choice. Utilization of genome-wide DSB sys-
tems that are capable of analyzing multiple site-specific DSBs in a
variety of chromatin contexts can overcome the normal limitations
of many DNA damaging agents that act in a non site-specific man-
ner. This type of system allows for the use of ChIP and genome-wide
sequencing to map histone modifications, including acetylations,
at multiple defined DSBs [17,72]. Genetic systems using histone
variant knockouts, including H2AX, in mammalian cells can also
provide insights into the function of site-specific acetylations using
complementation analysis of acetylation site mutants [43,73,74].
Development of these and additional approaches to analyze DNA
damage and histone acetylations across the genome, as well as
defining the acetyl-lysine interactome, will no doubt advance
our understanding of how DNA repair occurs within the context
of chromatin. HDAC, HAT and bromodomain containing proteins
are potential therapeutic anti-cancer targets due to their roles in
transcription, the radiosensitization effects observed upon their
 F. Gong, K.M. Miller / Mutation Research 750 (2013) 23–30
inhibition and importantly, their druggability due to the develop-
ment and availability of small molecule inhibitors targeting these
proteins [75–77]. The success of inhibitors of the BET family of
bromodomain-containing proteins, that include BRD4, in suppress-
ing growth in various cancer cell lines and murine cancer models
has raised considerable interest in targeting epigenetic readers in
cancer [78]. Interestingly, an isoform of BRD4 has been described
that acts as an inhibitor of the chromatin response to DNA damage
through an association with the condensin II complex [79]. These
functions of BRD4 required the lysine recognition bromodomain,
which is yet another example that highlights the critical relation-
ship between chromatin, histone acetylation and the DDR. Thus,
understanding the DDR and DNA repair within the context of chro-
matin will be critical in determining the utility of targeting the
DDR and histone acetylation pathways, including bromodomain
epigenetic readers, in diseases such as cancer.
Conflict of interest statement
The authors declare that there is no conflict of interest.
Acknowledgements
The Miller laboratory is in part supported by the Cancer Preven-
tion Research Institute of Texas (CPRIT). Dr. Kyle Miller is a CPRIT
scholar.
References
[1] S.P. Jackson, J. Bartek, The DNA-damage response in human biology and disease,
Nature 461 (2009) 1071–1078.
[2] A. Ciccia, S.J. Elledge, The DNA damage response: making it safe to play with
knives, Mol. Cell 40 (2010) 179–204.
[3] P. Huertas, DNA resection in eukaryotes: deciding how to fix the break, Nat.
Struct. Mol. Biol. 17 (2010) 11–16.
[4] A. Beucher, J. Birraux, L. Tchouandong, O. Barton, A. Shibata, S. Conrad, A.A.
Goodarzi, A. Krempler, P.A. Jeggo, M. Lobrich, ATM and Artemis promote homol-
ogous recombination of radiation-induced DNA double-strand breaks in G2,
EMBO J. 28 (2009) 3413–3427.
[5] M.R. Lieber, The mechanism of double-strand DNA break repair by the nonho-
mologous DNA end-joining pathway, Annu. Rev. Biochem. 79 (2010) 181–211.
[6] J.R. Chapman, M.R. Taylor, S.J. Boulton, Playing the end game: DNA double-
strand break repair pathway choice, Mol. Cell 47 (2012) 497–510.
[7] G. Soria, S.E. Polo, G. Almouzni, Prime, repair, restore: the active role of chro-
matin in the DNA damage response, Mol. Cell 46 (2012) 722–734.
[8] A. Gospodinov, Z. Herceg, Shaping chromatin for repair, Mutat. Res. 752 (2013)
45–60.
[9] B.D. Price, A.D. D’Andrea, Chromatin remodeling at DNA double-strand breaks,
Cell 152 (2013) 1344–1354.
[10] D. Rossetto, A.W. Truman, S.J. Kron, J. Cote, Epigenetic modifications in double-
strand break DNA damage signaling and repair, Clin. Cancer Res. 16 (2010)
4543–4552.
[11] Y. Xu, B.D. Price, Chromatin dynamics and the repair of DNA double strand
breaks, Cell Cycle 10 (2011) 261–267.
[12] R.D. Kornberg, Chromatin structure: a repeating unit of histones and DNA,
Science 184 (1974) 868–871.
[13] R. Margueron, D. Reinberg, Chromatin structure and the inheritance of epige-
netic information, Nat. Rev. Genet. 11 (2010) 285–296.
[14] T. Kouzarides, Chromatin modifications and their function, Cell 128 (2007)
693–705.
[15] E.I. Campos, D. Reinberg, Histones: annotating chromatin, Annu. Rev. Genet. 43
(2009) 559–599.
[16] T. Suganuma, J.L. Workman, Signals and combinatorial functions of histone
modifications, Annu. Rev. Biochem. 80 (2011) 473–499.
[17] K.M. Miller, S.P. Jackson, Histone marks: repairing DNA breaks within the con-
text of chromatin, Biochem. Soc. Trans. 40 (2012) 370–376.
[18] M.D. Shahbazian, M. Grunstein, Functions of site-specific histone acetylation
and deacetylation, Annu. Rev. Biochem. 76 (2007) 75–100.
[19] A.J. Ruthenburg, H. Li, D.J. Patel, C.D. Allis, Multivalent engagement of chromatin
modifications by linked binding modules, Nat. Rev. Mol. Cell Biol. 8 (2007)
983–994.
[20] A.J. Bannister, P. Zegerman, J.F. Partridge, E.A. Miska, J.O. Thomas, R.C. Allshire,
T. Kouzarides, Selective recognition of methylated lysine 9 on histone H3 by
the HP1 chromo domain, Nature 410 (2001) 120–124.
[21] S.I. Grewal, S. Jia, Heterochromatin revisited, Nat. Rev. Genet. 8 (2007) 35–46.
29
[22] V.G. Allfrey, R. Faulkner, A.E. Mirsky, Acetylation and methylation of histones
and their possible role in the regulation of RNA synthesis, Proc. Natl. Acad. Sci.
U. S. A. 51 (1964) 786–794.
[23] Z. Zhang, M. Tan, Z. Xie, L. Dai, Y. Chen, Y. Zhao, Identification of lysine suc-
cinylation as a new post-translational modification, Nat. Chem. Biol. 7 (2011)
58–63.
[24] J.E. Brownell, J. Zhou, T. Ranalli, R. Kobayashi, D.G. Edmondson, S.Y. Roth, C.D.
Allis, Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p link-
ing histone acetylation to gene activation, Cell 84 (1996) 843–851.
[25] J. Taunton, C.A. Hassig, S.L. Schreiber, A mammalian histone deacetylase related
to the yeast transcriptional regulator Rpd3p, Science 272 (1996) 408–411.
[26] K.K. Lee, J.L. Workman, Histone acetyltransferase complexes: one size doesn’t
fit all, Nat. Rev. Mol. Cell Biol. 8 (2007) 284–295.
[27] Y. Doyon, W. Selleck, W.S. Lane, S. Tan, J. Cote, Structural and functional conser-
vation of the NuA4 histone acetyltransferase complex from yeast to humans,
Mol. Cell. Biol. 24 (2004) 1884–1896.
[28] T. Ikura, S. Tashiro, A. Kakino, H. Shima, N. Jacob, R. Amunugama, K. Yoder, S.
Izumi, I. Kuraoka, K. Tanaka, H. Kimura, M. Ikura, S. Nishikubo, T. Ito, A. Muto, K.
Miyagawa, S. Takeda, R. Fishel, K. Igarashi, K. Kamiya, DNA damage-dependent
acetylation and ubiquitination of H2AX enhances chromatin dynamics, Mol.
Cell. Biol. 27 (2007) 7028–7040.
[29] X.J. Yang, E. Seto, The Rpd3/Hda1 family of lysine deacetylases: from bacteria
and yeast to mice and men, Nat. Rev. Mol. Cell Biol. 9 (2008) 206–218.
[30] J.L. Feldman, K.E. Dittenhafer-Reed, J.M. Denu, Sirtuin catalysis and regulation,
J. Biol. Chem. 287 (2012) 42419–42427.
[31] Y. Sun, X. Jiang, B.D. Price, Tip60: connecting chromatin to DNA damage
signaling, Cell Cycle 9 (2010) 930–936.
[32] K.H. Vousden, C. Prives, Blinded by the light: the growing complexity of p53,
Cell 137 (2009) 413–431.
[33] B. Ramanathan, M.J. Smerdon, Changes in nuclear protein acetylation in u.v.-
damaged human cells, Carcinogenesis 7 (1986) 1087–1094.
[34] B. Ramanathan, M.J. Smerdon, Enhanced DNA repair synthesis in hyperacety-
lated nucleosomes, J. Biol. Chem. 264 (1989) 11026–11034.
[35] M.J. Smerdon, DNA repair and the role of chromatin structure, Curr. Opin. Cell
Biol. 3 (1991) 422–428.
[36] R. Guo, J. Chen, D.L. Mitchell, D.G. Johnson, GCN5 and E2F1 stimulate nucleotide
excision repair by promoting H3K9 acetylation at sites of damage, Nucleic Acids
Res. 39 (2011) 1390–1397.
[37] J.V. Tjeertes, K.M. Miller, S.P. Jackson, Screen for DNA-damage-responsive his-
tone modifications identifies H3K9Ac and H3K56Ac in human cells, EMBO J. 28
(2009) 1878–1889.
[38] A. Battu, A. Ray, A.A. Wani, ASF1A and ATM regulate H3K56-mediated cell-cycle
checkpoint recovery in response to UV irradiation, Nucleic Acids Res. 39 (2011)
7931–7945.
[39] E.P. Rogakou, D.R. Pilch, A.H. Orr, V.S. Ivanova, W.M. Bonner, DNA double-
stranded breaks induce histone H2AX phosphorylation on serine 139, J. Biol.
Chem. 273 (1998) 5858–5868.
[40] W.M. Bonner, C.E. Redon, J.S. Dickey, A.J. Nakamura, O.A. Sedelnikova, S. Solier,
Y. Pommier, GammaH2AX and cancer, Nat. Rev. Cancer 8 (2008) 957–967.
[41] K. Yamagata, I. Kitabayashi, Sirt1 physically interacts with Tip60 and nega-
tively regulates Tip60-mediated acetylation of H2AX, Biochem. Biophys. Res.
Commun. 390 (2009) 1355–1360.
[42] X. Jiang, Y. Xu, B.D. Price, Acetylation of H2AX on lysine 36 plays a key role in the
DNA double-strand break repair pathway, FEBS Lett. 584 (2010) 2926–2930.
[43] A. Xie, S. Odate, G. Chandramouly, R. Scully, H2AX post-translational modifica-
tions in the ionizing radiation response and homologous recombination, Cell
Cycle 9 (2010) 3602–3610.
[44] J.J. Wyrick, M.A. Parra, The role of histone H2A and H2B post-translational mod-
ifications in transcription: a genomic perspective, Biochim. Biophys. Acta 1789
(2009) 37–44.
[45] T. Ikura, V.V. Ogryzko, M. Grigoriev, R. Groisman, J. Wang, M. Horikoshi, R. Scully,
J. Qin, Y. Nakatani, Involvement of the TIP60 histone acetylase complex in DNA
repair and apoptosis, Cell 102 (2000) 463–473.
[46] A. Gupta, G.G. Sharma, C.S. Young, M. Agarwal, E.R. Smith, T.T. Paull, J.C. Lucch-
esi, K.K. Khanna, T. Ludwig, T.K. Pandita, Involvement of human MOF in ATM
function, Mol. Cell. Biol. 25 (2005) 5292–5305.
[47] S. Jha, E. Shibata, A. Dutta, Human Rvb1/Tip49 is required for the histone
acetyltransferase activity of Tip60/NuA4 and for the downregulation of phos-
phorylation on H2AX after DNA damage, Mol. Cell. Biol. 28 (2008) 2690–2700.
[48] R. Murr, J.I. Loizou, Y.G. Yang, C. Cuenin, H. Li, Z.Q. Wang, Z. Herceg, Histone
acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of
DNA double-strand breaks, Nat. Cell Biol. 8 (2006) 91–99.
[49] Y. Sun, X. Jiang, Y. Xu, M.K. Ayrapetov, L.A. Moreau, J.R. Whetstine, B.D. Price,
Histone H3 methylation links DNA damage detection to activation of the
tumour suppressor Tip60, Nat. Cell Biol. 11 (2009) 1376–1382.
[50] Y. Xu, Y. Sun, X. Jiang, M.K. Ayrapetov, P. Moskwa, S. Yang, D.M. Weinstock, B.D.
Price, The p400 ATPase regulates nucleosome stability and chromatin ubiquit-
ination during DNA repair, J. Cell Biol. 191 (2010) 31–43.
[51] A. Kaidi, S.P. Jackson, KAT5 tyrosine phosphorylation couples chromatin
sensing to ATM signalling, Nature 498 (2013) 70–74.
[52] H. Ogiwara, A. Ui, A. Otsuka, H. Satoh, I. Yokomi, S. Nakajima, A. Yasui, J.
Yokota, T. Kohno, Histone acetylation by CBP and p300 at double-strand break
sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-
homologous end joining factors, Oncogene 30 (2011) 2135–2146.
[53] X. Li, C.A. Corsa, P.W. Pan, L. Wu, D. Ferguson, X. Yu, J. Min, Y. Dou, MOF and
H4 K16 acetylation play important roles in DNA damage repair by modulating
30 F. Gong, K.M. Miller / Mutation Research 750 (2013) 23–30
recruitment of DNA damage repair protein Mdc1, Mol. Cell. Biol. 30 (2010)
5335–5347.
[54] K.M. Miller, J.V. Tjeertes, J. Coates, G. Legube, S.E. Polo, S. Britton, S.P. Jackson,
Human HDAC1 and HDAC2 function in the DNA-damage response to promote
DNA nonhomologous end-joining, Nat. Struct. Mol. Biol. 17 (2010) 1144–1151.
[55] O.M. Dovey, C.T. Foster, N. Conte, S.A. Edwards, J.M. Edwards, R. Singh, G. Vas-
siliou, A. Bradley, S.M. Cowley, Histone deacetylase 1 and 2 are essential for
normal T-cell development and genomic stability in mice, Blood 121 (2013)
1335–1344.
[56] J. Tang, N.W. Cho, G. Cui, E.M. Manion, N.M. Shanbhag, M.V. Botuyan, G. Mer, R.A.
Greenberg, Acetylation limits 53BP1 association with damaged chromatin to
promote homologous recombination, Nat. Struct. Mol. Biol. 20 (2013) 317–325.
[57] K.Y. Hsiao, C.A. Mizzen, Histone H4 deacetylation facilitates 53BP1 DNA damage
signaling and double-strand break repair, J. Mol. Cell Biol. 5 (2013) 157–165.
[58] M. Shogren-Knaak, H. Ishii, J.M. Sun, M.J. Pazin, J.R. Davie, C.L. Peterson, His-
tone H4-K16 acetylation controls chromatin structure and protein interactions,
Science 311 (2006) 844–847.
[59] Y.C. Kim, G. Gerlitz, T. Furusawa, F. Catez, A. Nussenzweig, K.S. Oh, K.H. Krae-
mer, Y. Shiloh, M. Bustin, Activation of ATM depends on chromatin interactions
occurring before induction of DNA damage, Nat. Cell Biol. 11 (2009) 92–96.
[60] C. Das, M.S. Lucia, K.C. Hansen, J.K. Tyler, CBP/p300-mediated acetylation of
histone H3 on lysine 56, Nature 459 (2009) 113–117.
[61] R.A. McCord, E. Michishita, T. Hong, E. Berber, L.D. Boxer, R. Kusumoto, S. Guan,
X. Shi, O. Gozani, A.L. Burlingame, V.A. Bohr, K.F. Chua, SIRT6 stabilizes DNA-
dependent protein kinase at chromatin for DNA double-strand break repair,
Aging (Albany, N.Y.) (Milano) 1 (2009) 109–121.
[62] H.S. Lee, J.H. Park, S.J. Kim, S.J. Kwon, J. Kwon, A cooperative activation loop
among SWI/SNF, gamma-H2AX and H3 acetylation for DNA double-strand
break repair, EMBO J. 29 (2010) 1434–1445.
[63] C. Alabert, A. Groth, Chromatin replication and epigenome maintenance, Nat.
Rev. Mol. Cell. Biol. 13 (2012) 153–167.
[64] B.M. Sirbu, F.B. Couch, J.T. Feigerle, S. Bhaskara, S.W. Hiebert, D. Cortez, Analysis
of protein dynamics at active, stalled, and collapsed replication forks, Genes
Dev. 25 (2011) 1320–1327.
[65] S. Bhaskara, S.K. Knutson, G. Jiang, M.B. Chandrasekharan, A.J. Wilson, S. Zheng,
A. Yenamandra, K. Locke, J.L. Yuan, A.R. Bonine-Summers, C.E. Wells, J.F. Kaiser,
M.K. Washington, Z. Zhao, F.F. Wagner, Z.W. Sun, F. Xia, E.B. Holson, D. Khabele,
S.W. Hiebert, Hdac3 is essential for the maintenance of chromatin structure
and genome stability, Cancer Cell 18 (2010) 436–447.
[66] P. Oberdoerffer, S. Michan, M. McVay, R. Mostoslavsky, J. Vann, S.K. Park, A.
Hartlerode, J. Stegmuller, A. Hafner, P. Loerch, S.M. Wright, K.D. Mills, A. Bonni,
B.A. Yankner, R. Scully, T.A. Prolla, F.W. Alt, D.A. Sinclair, SIRT1 redistribution on
chromatin promotes genomic stability but alters gene expression during aging,
Cell 135 (2008) 907–918.
[67] W. Dang, K.K. Steffen, R. Perry, J.A. Dorsey, F.B. Johnson, A. Shilatifard, M. Kae-
berlein, B.K. Kennedy, S.L. Berger, Histone H4 lysine 16 acetylation regulates
cellular lifespan, Nature 459 (2009) 802–807.
[68] R.J. O’Sullivan, S. Kubicek, S.L. Schreiber, S.L. Schreiber, KarlsederF J., Reduced
histone biosynthesis and chromatin changes arising from a damage signal at
telomeres, Nat. Struct. Mol. Biol. 17 (2010) 1218–1225.
[69] Z. Wang, C. Zang, K. Cui, D.E. Schones, A. Barski, W. Peng, K. Zhao, Genome-wide
mapping of HATs and HDACs reveals distinct functions in active and inactive
genes, Cell 138 (2009) 1019–1031.
[70] J.H. Waterborg, Dynamics of histone acetylation in vivo. A function for acety-
lation turnover? Biochem. Cell Biol. 80 (2002) 363–378.
[71] M.X. Qian, Y. Pang, C.H. Liu, K. Haratake, B.Y. Du, D.Y. Ji, G.F. Wang, Q.Q. Zhu, W.
Song, Y. Yu, X.X. Zhang, H.T. Huang, S. Miao, L.B. Chen, Z.H. Zhang, Y.N. Liang,
S. Liu, H. Cha, D. Yang, Y. Zhai, T. Komatsu, F. Tsuruta, H. Li, C. Cao, W. Li, G.H.
Li, Y. Cheng, T. Chiba, L. Wang, A.L. Goldberg, Y. Shen, X.B. Qiu, Acetylation-
mediated proteasomal degradation of core histones during DNA repair and
spermatogenesis, Cell 153 (2013) 1012–1024.
[72] J.S. Iacovoni, P. Caron, I. Lassadi, E. Nicolas, L. Massip, D. Trouche, G. Legube,
High-resolution profiling of gammaH2AX around DNA double strand breaks in
the mammalian genome, EMBO J. 29 (2010) 1446–1457.
[73] Y. Xu, M.K. Ayrapetov, C. Xu, O. Gursoy-Yuzugullu, Y. Hu, B.D. Price, Histone
H2A.Z. controls a critical chromatin remodeling step required for DNA double-
strand break repair, Mol. Cell 48 (2012) 723–733.
[74] W.T. Chen, A. Alpert, C. Leiter, F. Gong, S.P. Jackson, K.M. Miller, Systematic
identification of functional residues in mammalian histone H2AX, Mol. Cell.
Biol. 33 (2013) 111–126.
[75] I. Barbieri, E. Cannizzaro, M.A. Dawson, Bromodomains as therapeutic targets
in cancer, Brief. Funct. Genomics 12 (2013) 219–230.
[76] V. Di Cerbo, R. Schneider, Cancers with wrong HATs: the impact of acetylation,
Brief. Funct. Genomics 12 (2013) 231–243.
[77] B. Groselj, N.L. Sharma, F.C. Hamdy, M. Kerr, A.E. Kiltie, Histone deacetylase
inhibitors as radiosensitisers: effects on DNA damage signalling and repair, Br.
J. Cancer 108 (2013) 748–754.
[78] M.A. Dawson, T. Kouzarides, B.J. Huntly, Targeting epigenetic readers in cancer,
New Engl. J. Med. 367 (2012) 647–657.
[79] S.R. Floyd, M.E. Pacold, Q. Huang, S.M. Clarke, F.C. Lam, I.G. Cannell, B.D. Bryson,
J. Rameseder, M.J. Lee, E.J. Blake, A. Fydrych, R. Ho, B.A. Greenberger, G.C. Chen,
A. Maffa, A.M. Del Rosario, D.E. Root, A.E. Carpenter, W.C. Hahn, D.M. Sabatini,
C.C. Chen, F.M. White, J.E. Bradner, M.B. Yaffe, The bromodomain protein Brd4
insulates chromatin from DNA damage signalling, Nature 498 (2013) 246–250.
[80] E.A. Lebel, P. Boukamp, S.T. Tafrov, Irradiation with heavy-ion particles changes
the cellular distribution of human histone acetyltransferase HAT1, Mol. Cell.
Biochem. 339 (2010) 271–284.
[81] I.M. Love, P. Sekaric, D. Shi, S.R. Grossman, E.J. Androphy, The histone
acetyltransferase PCAF regulates p21 transcription through stress-induced
acetylation of histone H3, Cell Cycle 11 (2012) 2458–2466.
[82] M. Tillhon, O. Cazzalini, T. Nardo, D. Necchi, S. Sommatis, L.A. Stivala, A.I. Sco-
vassi, E. Prosperi, p300/CBP acetyl transferases interact with and acetylate the
nucleotide excision repair factor XPG, DNA Repair 11 (2012) 844–852.
[83] R.K. Vempati, R.S. Jayani, D. Notani, A. Sengupta, S. Galande, D. Haldar, p300-
mediated acetylation of histone H3 lysine 56 functions in DNA damage
response in mammals, J. Biol. Chem. 285 (2010) 28553–28564.
[84] M.K. Kim, J.M. Shin, H.C. Eun, J.H. Chung, The role of p300 histone acetyltrans-
ferase in UV-induced histone modifications and MMP-1 gene transcription,
PloS ONE 4 (2009) e4864.
[85] E.R. Jang, J.D. Choi, J.S. Lee, Acetyltransferase p300 regulates NBS1-mediated
DNA damage response, FEBS Lett. 585 (2011) 47–52.
[86] C.P. Rubbi, J. Milner, p53 is a chromatin accessibility factor for nucleotide exci-
sion repair of DNA damage, EMBO J. 22 (2003) 975–986.
[87] A.M. Buchmann, J.R. Skaar, J.A. DeCaprio, Activation of a DNA damage check-
point response in a TAF1-defective cell line, Mol. Cell. Biol. 24 (2004)
5332–5339.
[88] Y. Sun, X. Jiang, S. Chen, N. Fernandes, B.D. Price, A role for the Tip60 histone
acetyltransferase in the acetylation and activation of ATM, Proc. Natl. Acad. Sci.
U. S. A. 102 (2005) 13182–13187.
[89] G.G. Sharma, S. So, A. Gupta, R. Kumar, C. Cayrou, N. Avvakumov, U. Bhadra,
R.K. Pandita, M.H. Porteus, D.J. Chen, J. Cote, T.K. Pandita, MOF and histone H4
acetylation at lysine 16 are critical for DNA damage response and double-strand
break repair, Mol. Cell. Biol. 30 (2010) 3582–3595.
[90] C. Cotta-Ramusino, E.R. McDonald 3rd, K. Hurov, M.E. Sowa, J.W. Harper, S.J.
Elledge, A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1
interacting protein required for ATR signaling, Science 332 (2011) 1313–1317.
[91] G.D. Kao, W.G. McKenna, M.G. Guenther, R.J. Muschel, M.A. Lazar, T.J. Yen, His-
tone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response,
J. Cell Biol. 160 (2003) 1017–1027.
[92] V. Basile, R. Mantovani, C. Imbriano, DNA damage promotes histone deacetylase
4 nuclear localization and repression of G2/M promoters, via p53 C-terminal
lysines, J. Biol. Chem. 281 (2006) 2347–2357.
[93] S. Kotian, S. Liyanarachchi, A. Zelent, J.D. Parvin, Histone deacetylases 9 and
10 are required for homologous recombination, J. Biol. Chem. 286 (2011)
7722–7726.
[94] H.M. O’Hagan, H.P. Mohammad, S.B. Baylin, Double strand breaks can initiate
gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous
promoter CpG island, PLoS Genet. 4 (2008) e1000155.
[95] R.H. Wang, K. Sengupta, C. Li, H.S. Kim, L. Cao, C. Xiao, S. Kim, X. Xu, Y. Zheng, B.
Chilton, R. Jia, Z.M. Zheng, E. Appella, X.W. Wang, T. Ried, C.X. Deng, Impaired
DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant
mice, Cancer Cell 14 (2008) 312–323.
[96] A. Kaidi, B.T. Weinert, C. Choudhary, S.P. Jackson, Human SIRT6 promotes DNA
end resection through CtIP deacetylation, Science 329 (2010) 1348–1353.
[97] R. Mostoslavsky, K.F. Chua, D.B. Lombard, W.W. Pang, M.R. Fischer, L. Gellon, P.
Liu, G. Mostoslavsky, S. Franco, M.M. Murphy, K.D. Mills, P. Patel, J.T. Hsu, A.L.
Hong, E. Ford, H.L. Cheng, C. Kennedy, N. Nunez, R. Bronson, D. Frendewey, W.
Auerbach, D. Valenzuela, M. Karow, M.O. Hottiger, S. Hursting, J.C. Barrett, L.
Guarente, R. Mulligan, B. Demple, G.D. Yancopoulos, F.W. Alt, Genomic insta-
bility and aging-like phenotype in the absence of mammalian SIRT6, Cell 124
(2006) 315–329.
[98] C.A. Musselman, M.E. Lalonde, J. Cote, T.G. Kutateladze, Perceiving the epi-
genetic landscape through histone readers, Nat. Struct. Mol. Biol. 19 (2012)
1218–1227.