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Stop relaxing: How DNA damage-induced chromatin compaction may affect

epigenetic integrity and disease

Article in Molecular & Cellular Oncology · December 2014

DOI: 10.4161/23723548.2014.970952

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Philipp Oberdoerffer
Johns Hopkins Medicine
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Stop relaxing: How DNA damage-induced chromatin
compaction may affect epigenetic integrity and disease
a
Philipp Oberdoerffer
a
Laboratory of Receptor Biology and Gene Expression. National Cancer Institute; NIH;
Bethesda, MD USA
Accepted author version posted online: 01 Dec 2014.

To cite this article: Philipp Oberdoerffer (2015) Stop relaxing: How DNA damage-induced chromatin compaction may affect
epigenetic integrity and disease, Molecular & Cellular Oncology, 2:1, e970952, DOI: 10.4161/23723548.2014.970952

To link to this article: http://dx.doi.org/10.4161/23723548.2014.970952

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 AUTHOR'S VIEW
Molecular & Cellular Oncology 2:1, e970952; January/February/March 2015; Published with license by Taylor & Francis Group, LLC

Stop relaxing: How DNA damage-induced

chromatin compaction may affect epigenetic
integrity and disease
Philipp Oberdoerffer*
Laboratory of Receptor Biology and Gene Expression. National Cancer Institute; NIH; Bethesda, MD USA

Keywords: DNA repair, chromatin, macroH2A1, senescence, replication stress

DNA damage is widely recognized for its potential to impair epigenetic integrity. Epigenetic defects are closely
associated with a variety of diseases. We have recently uncovered DNA double-strand break-induced chromatin
condensation as a critical modulator of repair outcome. Here, we discuss the possible implications for cell functions
beyond repair.
Downloaded by [76.100.201.38] at 14:09 26 February 2015

The tightly regulated organization of
genomic DNA in nuclear space is essential
for the control of gene expression, DNA
replication, and genome stability. To
achieve this level of organization, eukaryotic
DNA is packaged into chromatin, a higher
order ribonucleic acid-protein complex
comprised of a DNA/histone core and a
plethora of accessory proteins, RNAs, and
modifying enzymes. Recent comparative
genome-wide analyses highlight the diverse,
and often evolutionarily conserved, ele-
ments that contribute to metazoan chroma-
tin organization.1 It is therefore not
surprising that aberrant cellular function,
disease, and malignant transformation are
associated with profound alterations in the
epigenetic landscape.2,3
Over the past decade it has become
apparent that DNA damage poses a signif-
icant threat to the integrity of our epige-
nomes. DNA damage results in a range of
chromatin alterations at the sites of DNA
lesions that involve changes in histone
modifications, nucleosome remodeling,
and histone (variant) exchange.4 The dra-
matic impact of DNA damage on chroma-
tin is perhaps best exemplified at DNA
double-strand breaks (DSBs), which pro-
mote an immediate and expansive
reorganization of the surrounding chro-
matin structure to render damaged DNA
accessible for repair factors.4 We recently
showed that this process is followed by an
unexpected phase of prolonged chromatin
re-condensation, which is initiated well
before recruitment of repair factors is
completed and is in fact essential for effi-
cient accumulation of the tumor suppres-
sor and DSB repair mediator BRCA1.5
DSB-induced chromatin condensation
involves the coordinated, DNA damage
signaling-dependent recruitment of the
macro-histone variant macroH2A1
(encoded by H2AFY) and the histone
methyltransferase PRDM2, which in turn
promote dimethylation of lysine 9 on his-
tone H3 (H3K9me2) flanking the DSB.
Although the importance of this process
for accurate genome maintenance has
been discussed previously,5 its implica-
tions for the epigenetic integrity of the cell
remain unclear. Several intriguing possi-
bilities are considered below.
Both macro-histones and H3K9 meth-
ylation have long been associated with cel-
lular processes that involve the formation
of repressive chromatin, such as gene
silencing and X chromosome inactivation.
By analogy, the macroH2A1/PRDM2-
dependent modulation of DSB-proximal
chromatin results in condensation of
nucleosomes that can be detected up to
several hundred kilobases from the DSB
site.5 Both macroH2A1 and H3K9me2
persist for hours after DNA damage, a
time frame that is sufficient to cause
potentially harmful changes in chromatin
structure and/or gene expression. Notably,
DSBs were found to promote transcrip-
tional silencing in cis to the site of dam-
age,4 and it will be interesting to
determine whether macroH2A1/
PRDM2-dependent chromatin compac-
tion is required for this process (Fig. 1A).
In addition, DNA repair was found to
promote the redistribution of repair-rele-
vant chromatin modifiers from undam-
aged to damaged chromatin, thus
accounting for epigenetic gene deregula-
tion beyond the sites of damage.6 Both
macroH2A1 and PRDM2 were reported
to act as tumor suppressors and their
recruitment to DSBs may perturb these
functions by depleting macroH2A1 and/
or PRDM2 from the genomic loci or pro-
tein complexes they normally associate
with. Consistent with this notion, a reduc-
tion in macroH2A1 was recently found to
promote melanoma progression by

© Philipp Oberdoerffer
*Correspondence to: Philipp Oberdoerffer; Email: Philipp.Oberdoerffer@nih.gov
Submitted: 09/11/2014; Revised: 09/12/2014; Accepted: 09/13/2014
http://dx.doi.org/10.4161/23723548.2014.970952
This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/
by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The
moral rights of the named author(s) have been asserted.

www.tandfonline.com Molecular & Cellular Oncology e970952-1

Downloaded by [76.100.201.38] at 14:09 26 February 2015

Figure 1. Epigenetic consequences of DNA double-strand break (DSB)-induced chromatin compaction. (A) DSBs promote concomitant macroH2A1 accu-
mulation, chromatin condensation, and BRCA1 accumulation. DSBs may thereby cause transient or persistent changes in nuclear chromatin organization
and the expression of break-proximal genes. (B) Stalled replication forks trigger recruitment of BRCA1 to promote fork rescue; macroH2A1 may be
recruited to facilitate BRCA1 accumulation. Continued replication stress can trigger cellular senescence and the accumulation of macroH2A1-containing,
senescence-associated heterochromatin foci (SAHFs). MacroH2A1 may provide a link between stalled replication forks and SAHF formation. A schematic
of nuclear changes in response to DSBs (lightning bolt) or replication stress (burst) is shown. Gray ovals, repressive chromatin domains; green oval,
SAHF.

causing direct transcriptional upregulation
of the colorectal cancer oncogene cyclin-
dependent kinase 8 (CDK8).7 Given that
cells are continuously exposed to both
exogenous and endogenous sources of
DSBs, it seems plausible that even tran-
sient macroH2A1/PRDM2-dependent
chromatin changes may result in chronic
epigenetic defects. This could be particu-
larly relevant during aging, which displays
a continuous increase in DNA damage
across the genome.
Macro-histones and H3K9 methyla-
tion have also been implicated in cellular
senescence, an irreversible proliferative
arrest that is thought to contribute to
tumor suppression and possibly aging.
Specifically, macroH2A1 accumulates at
so-called senescence-associated hetero-
chromatin foci (SAHFs), which are
enriched in heterochromatin protein 1
and K9-methylated histone H3.8 SAHFs
reflect an extensive transformation of tran-
scriptionally active euchromatin into a less
accessible heterochromatic state. This pro-
cess has been linked to silencing of retino-
blastoma (RB)/E2F transcription factor-
regulated genes and may thereby contrib-
ute to senescence-associated cell cycle
arrest.9 Although the molecular basis for
SAHF formation remains elusive, DNA
replication stress and the concomitant
activation of the DNA damage sensor
ATR kinase have been positively corre-
lated with this process. Moreover, pro-
longed replication stress can result in
genomic aberrations including common
fragile site instability and DSB formation,
thereby adding to the continued activation
of the DNA damage response that appears
to drive senescence.9 Notably, BRCA1
was recently reported to play an important
role in the resolution of stalled replication
forks, a main source of replication stress.10
Given the newly identified role of mac-
roH2A1 in BRCA1-dependent genome
maintenance following DSB formation, it
is tempting to speculate that macroH2A1
may be equally involved in preventing
aberrant fork stalling. By extension, mac-
roH2A1 may thus provide a mechanistic
link between replication stress and the for-
mation of SAHFs (Fig. 1B). However,
more work is needed to dissect the impact

e970952-2 Molecular & Cellular Oncology Volume 2 Issue 1

 of macroH2A1 and/or PRDM2 on cellu-
lar senescence in the context of DNA
damage signaling.
Taken together, these findings suggest
that DNA damage-associated formation
of repressive chromatin is likely to have
significant implications for the epigenetic
integrity of eukaryotic cells. Its functional
consequences may range from the
formation of senescence-associated
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Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were
disclosed.
Funding
This work was supported by the Intra-
mural Research Program of the National
Cancer Institute, NIH.
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