Download The role of DNA damage in laminopathy progeroid syndromes

Nuclear Envelope Disease and Chromatin Organization
The role of DNA damage in laminopathy progeroid
syndromes
Christopher J. Hutchison1
School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, U.K.
Abstract
Progeroid laminopathies are characterized by the abnormal processing of lamin A, the appearance of
misshapen nuclei, and the accumulation and persistence of DNA damage. In the present article, I consider
the contribution of defective DNA damage pathways to the pathology of progeroid laminopathies. Defects
in DNA repair pathways appear to be caused by a combination of factors. These include abnormal epigenetic
modifications of chromatin that are required to recruit DNA repair pathways to sites of DNA damage,
abnormal recruitment of DNA excision repair proteins to sites of DNA double-strand breaks, and unrepairable
ROS (reactive oxygen species)-induced DNA damage. At least two of these defective processes offer the
potential for novel therapeutic approaches.
The progeroid laminopathies and prelamin
A toxicity
The progeroid laminopathies include HGPS (Hutchinson–
Gilford progeria syndrome), atypical Werner’s syndrome,
MAD (mandibuloacral dysplasia) and RD (restrictive
dermopathy) [1]. All of these diseases have been linked to
abnormal post-translational processing of prelamin A, which
promotes nuclear shape abnormalities and cellular toxicity
[2–5]. The initial post-translational processing of lamin A
is now well-characterized. Lamin A is first translated as a
precursor molecule termed prelamin A that possesses a Cterminal motif, CaaX (where a is an aliphatic residue), which
is a receptor site for protein farnesylation and methylation.
Initially, the cysteine residue is farnesylated before the final
three amino acids are proteolytically cleaved. This is followed
by methylation of the now C-terminal cysteine residue before
the partially processed prelamin A is translocated to the
INM (inner nuclear membrane). Once at the INM,
the final 15 amino acids are cleaved by the ZmpSte24
(zinc metallopeptidase Ste24 homologue) protease to generate
mature lamin A [3,6]. A majority (∼ 80%) of mutations giving
rise to HGPS are caused by silent mutations in exon 11
of LMNA that activates a cryptic splice site and permits
synthesis of an alternatively splice variant of prelamin A,
termed progerin, which lacks the ZmpSte24 cleavage site and
consequently cannot undergo the final processing step. This
in turn means that progerin is permanently farnesylated [7,8].
The representation of progerin in fibroblasts from HGPS
Key words: DNA damage response, Hutchinson–Gilford progeria syndrome (HGPS), lamin,
laminopathy, progeria, reactive oxygen species (ROS).
Abbreviations used: ATM, ataxia telangiectasia mutated; ATR, ATM- and Rad3-related; 53BP1,
p53-binding protein 1; DDR, DNA damage response; DSB, double-strand break; FC-prelamin
A, prelamin A with farnesylated cysteine residue; FTI, farnesyltransferase inhibitor; HGPS,
Hutchinson–Gilford progeria syndrome; HP1, heterochromatin protein 1; INM, inner nuclear
membrane; MAD, mandibuloacral dysplasia; MEF, mouse embryonic fibroblast; NAC, Nacetylcysteine; NuRD, nucleosome remodelling and deacetylation; RBBP, retinoblastoma-binding
protein; RD, restrictive dermopathy; ROS, reactive oxygen species; siRNA, small interfering RNA;
XPA, xeroderma pigmentosum group A; ZmpSte24, zinc metallopeptidase Ste24 homologue.
1
email [email protected]
Biochem. Soc. Trans. (2011) 39, 1715–1718; doi:10.1042/BST20110700
patients increases with increasing passage number [9] and
this is thought to increase its toxic effects. In RD and MAD,
as well as in some cases of HGPS, the diseases are caused by
homozygous mutations in a conserved region of the gene
encoding the ZmpSte24 protease, and in fibroblasts from
these patients, the disease is caused by abnormal processing of
prelamin A, leading to the accumulation of a form of prelamin
A that retains the farnesylated cysteine residue (FCprelamin A) [10–12]. Some forms of HGPS (non-classical
HGPS) as well as atypical Werner’s syndrome are caused by
mutations in exons of LMNA encoding the rod domain of
lamins A and C [1] and do not give rise to splice site variants,
whereas other mutations occur in the BANF1 gene [encoding
the chromatin protein BAF (barrier to autointegration factor
1)] [13], suggesting that laminopathy progerias do not
necessarily all arise through the accumulation of farnesylated
forms of lamin A.
Despite reports of non-classical forms of HGPS, therapeutic approaches have centred on the use of drugs that inhibit
the farnesylation of both progerin and prelamin A. These
include the use of FTIs (farnesyltransferase inhibitors) as a
direct tool to inhibit farnesylation [2,4,5] or a combination
of aminobisphosphonates and statins, which act indirectly by
preventing the synthesis of precursors of farnesyl and geranyl
residues [14]. Both types of treatment do extend lifespan in
mouse models of HGPS [14] and are currently being used
in clinical trials.
DDR (DNA damage response) in progeroid
laminopathies
As stated above, the most obvious morphological feature of
the progeroid laminopathies is the appearance of misshapen
(or dysmorphic) nuclei in cells obtained from patients or in
cells that express progerin ectopically [9]. The presence of
dysmorphic nuclei can be ameliorated by growing cells in
media containing FTIs [2,4,5]. Another feature of fibroblasts
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Biochemical Society Transactions (2011) Volume 39, part 6
from progeroid laminopathy patients is the accumulation of
unrepaired DNA damage [15–17] and accelerated telomere
attrition [18,19]. The accumulation of unrepaired DNA
damage activates a checkpoint response that is characterized
by phosphorylation of both the ATM (ataxia telangiectasia
mutated) and ATR (ATM- and Rad3-related) checkpoint
kinases. Activation of checkpoint responses seems to underlie
the slow growth of HGPS fibroblasts in culture, since siRNA
(small interfering RNA) knockdown of ATM and ATR in
these cells restores replicative capacity [20]. In stark contrast
with nuclear shape abnormalities, accumulation of unrepaired
DNA damage is not reversed by treatment with FTIs [20]
and this finding is consistent with studies showing that the
accumulation of unfarnesylated forms of progerin in mice
still promotes aging phenotypes [21], whereas treatment of
Caenorhabditis elegans with FTIs limits the accumulation
of dysmophic nuclei, without extending lifespan [22]. These
findings argue strongly that processes other those promoting
the formation of dysmorphic nuclei account for the aging
phenotypes in laminopathy progerias and has led to a
number of investigations into the causes and effects of the
accumulation of unrepairable DNA damage in these diseases.
The first study revealing the increased sensitivity to
ionizing radiation and genome instability in a mouse model
of HGPS and fibroblasts from HGPS patients demonstrated
that the DDR was impaired and that this was characterized
by delayed recruitment of DNA damage proteins, including
53BP1 (p53-binding protein 1) and Rad50 to sites of
DNA damage [15]. The impaired DDR was correlated with
activation of p53-response pathways, although, curiously,
this occurred in the absence of increased levels of p53 or p53
phosphorylation [23]. DDRs are characterized by epigenetic
modification of chromosomes, including the accumulation
of the phosphorylated form of a histone H2A variant
H2AX at sites of DNA DSBs (double-strand breaks) [24]
and methylation of histone H3 and histone H4 [25,26].
A hallmark of fibroblasts from progeriod laminopathy
patients is the persistence of H2AX foci [15], altered
methylation of H3 and H4 and down-regulation of HP1
(heterochromatin protein 1) [27,28], which are all predicted
to lead to a loss of heterochromatin. The persistence of
H2AX foci is indicative of an accumulation of unrepaired
DSBs. However, there is now strong evidence that this
is underpinned by altered H3 methylation. The NuRD
(nucleosome remodelling and deacetylation) complex is a key
regulator of histone methylation [29]. Chromatin proteins
RBBP (retinoblastoma-binding protein) 4 and its paralogue RBBP7 are both components of the NuRD complex
and bind to the region of the lamin A tail domain, which
is lacking in progerin. The levels of both RBBP4 and
RBBP7 are reduced in HGPS fibroblasts compared with agematched control fibroblasts, and this loss is dependent upon
the presence of progerin. Interestingly, loss of RBBP4 and
RBBP7 precedes the accumulation of persistent H2AX foci,
and siRNA knockdown of RBBP4 and RBBP7 in normal
fibroblasts leads to decreased H3 methylation followed
by the accumulation of H2AX foci. Knockdown of other
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Authors Journal compilation components of the NuRD complex also promote the
accumulation of unrepaired DSBs [30]. In a more recent
study, hypoacetylation of H4 was observed in fibroblasts
from a ZmpSte24 − / − mouse. Hypoacetylation of H4 was
linked to loss of nuclear matrix association of the histone
acetyltransferase Mof. Importantly, overexpression of Mof
in ZmpSte24 − / − fibroblasts or treatment of the cells with
a histone deacetylase inhibitor promoted the recruitment
of DNA repair proteins to sites of DNA damage and
significantly decreased the rate of entry into a senescent
state [31]. Both of these studies therefore imply that the
impairment of the DDR, in the presence of either progerin or
FC-prelamin A, arises from defects in chromatin-remodelling
steps that precede the recruitment of DNA damage proteins
to sites of DNA repair.
Impairment of DDR in fibroblasts from HGPS and RD
patients appears to be also related to incorrect recognition of
types of DNA damage. As stated above, DSBs induced by
ionizing radiation in HGPS fibroblasts are characterized
by impaired recruitment of the DNA repair proteins
Rad50 and Rad51 [31]. Both HGPS and RD fibroblasts
accumulate DSBs during passage in culture, even in the
absence of mutagenesis, and therefore carry a mutational
load. Interestingly, when treated with genotoxic agents such
as camptothecin or etoposide, newly induced DSBs can be
repaired efficiently in both HGPS and RD fibroblasts [32,33].
In contrast, the accumulated load of DNA damage remains
unrepaired. These sites fail to recruit Rad50 and Rad51,
but instead recruit the DNA excision repair protein XPA
(xeroderma pigmentosum group A). Importantly, siRNA
knockdown of XPA in HGPS and RD fibroblasts partially
restores the ability of these cells to undergo DNA repair,
implying that the presence of XPA at sites of DSBs is involved
in the failure to recruit DSB proteins to those same sites [32].
In a separate study, loss of stability of the DNA repair
protein 53BP1 has been implicated in telomere erosion and
persistent DSBs at telomeric DNA. This study utilized MEFs
(mouse embryonic fibroblasts) from an Lmna − / − mouse. In
these MEFs, telomeric DNA was abnormally distributed in
the interphase nucleus being clustered towards the nuclear
periphery (although not located at the nuclear envelope)
compared with wild-type MEFs, in which telomeres
were distributed throughout the nucleus. This abnormal
distribution of telomeric DNA was correlated with a modest,
but significant, shortening of telomere length, but highly
significantly impaired H4 methylation and accumulation
of H2AX in telomeric chromatin [34]. Telomeric DNA
damage is repaired by NHEJ (non-homologous end-joining),
which is mediated by the DNA repair protein 53BP1 [35].
Consistent, with this finding, the overall levels of 53BP1 were
reduced in Lmna − / − MEFs [34].
ROS (reactive oxygen species) and
persistent DNA damage in HGPS and RD
Recent studies have reported on the increased sensitivity of
fibroblasts from progeria patients to oxidative stress [36].
Nuclear Envelope Disease and Chromatin Organization
Moreover, progerin has also been reported to promote the
accumulation of oxidized proteins in fibroblasts [37]. ROS
generation and imbalance is a major cause of DNA damage
[38] and could underlie the accumulation and persistence of
DSBs in HGPS and RD fibroblasts with increasing age in
culture. With this in mind, ROS levels and ROS sensitivity in
fibroblasts from HGPS and RD patients were investigated.
Significantly higher basal levels of ROS, as well as increased
sensitivity to ROS stimuli, were reported. Both of these
features could be ameliorated with a commonly used ROS
scavenger NAC (N-acetylcysteine). ROS stimulation led
to DNA damage, which was only partially repaired and
therefore increased the load of DSBs in HGPS and RD
fibroblasts. Interestingly, treatment of cells with NAC, before
ROS stimulation, permitted repair of all DSBs. Moreover,
growth of HGPS and RD fibroblasts in the presence of
NAC also significantly reduced the basal levels of DSBs. This
finding implies that the elevated basal levels of ROS in these
cells is the cause of the persistent DNA damage [33].
Links to normal aging
ROS generation and the accumulation of persistent DNA
damage have both been linked to cellular and organismal
aging [39,40]. Expression of progerin and prelamin A have
also been linked to cellular senescence and aging in normal
individuals [27,41]. It is therefore important to understand
whether the mechanisms underlying the impaired DDR
in laminopathy progerias also underlie the accumulation
of persistent DNA damage in normal aging. Components of
the NuRD complex, including RBBP4, RBBP7 and HP1, are
all depleted in fibroblasts from very old individuals relative
to fibroblasts from very young individuals, implying that at
least one of the chromatin-remodelling pathways necessary
for efficient DNA repair loses efficiency with increasing age
[30]. In contrast, fibroblasts from very old individuals do
not display increased basal levels of ROS or increased ROS
sensitivity when compared with fibroblasts from very young
individuals. Moreover, repair of ROS-induced DSBs is very
efficient in the same cells [33]. Thus the DNA repair defects in
laminopathy progeroid syndromes appear to be only a partial
phenocopy of normal aging.
New therapeutic targets
At least two of the DNA damage defects in progeroid laminopathies appear to offer novel targets for pharmacological
intervention. At present, the most successful therapies for
existing patients is a combination of aminobisphosphonates
and statins [14]. However, ZmpSte24 − / − mice that were
provided with a histone deacetylase inhibitor in their drinking
water displayed weight gain, increased bone density and
increased lifespan compared with untreated littermates [31].
Similarly, when grown in the presence of NAC, fibroblasts
from HGPS and RD patients displayed normal growth
kinetics and increased longevity [33]. Thus a combination of
therapeutic approaches, which includes targets in DNA repair
pathways, might offer significant improvements in quality of
life for patients with progeroid laminopathies.
Acknowledgements
I thank Shane Richards, Joanne Muter and Ian Gibbs-Seymour for
their contribution to work on DNA repair pathways.
Funding
Work in my laboratory is supported by the Association for
International Cancer Research, the JGW Patterson Foundation, the
Wellcome Trust and ONE NE.
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Received 5 August 2011
doi:10.1042/BST20110700