Review

Preserving the genome by regulating

chromatin association with the nuclear
envelope
Rodrigo Bermejo1*, Amit Kumar1 and Marco Foiani1,2
1

IFOM (Fondazione Istituto FIRC di Oncologia Molecolare) at the IFOMEuropean Institute of Oncology (IEO) Campus,
Via Adamello 16, 20139 Milan, Italy
2
DSBB (Dipartimento di Scienze Biomolecolari e Biotecnologie), Universita` degli Studi di Milano, Milan, Italy

The nuclear envelope compartmentalizes chromatin

within eukaryotic cells and influences diverse cellular
functions by controlling nucleocytoplasmic trafficking.
Recent evidence has revealed the importance of interactions between chromatin and nuclear envelope components in the maintenance of genome integrity.
Nuclear pore complexes (NPCs), traditionally regarded
as transport gateways, have emerged as specialized
hubs involved in organizing genome architecture, influencing DNA topology, and modulating DNA repair. Here,
we review the interplay between the nuclear envelope,
chromatin and DNA damage checkpoint pathways, and
discuss the physiological and pathological implications
of these associations.
A role for nuclear envelope in controlling genome
integrity
NPCs are sites of active nucleocytoplasmic trafficking and
pillars of nuclear envelope architecture. NPCs also represent specialized hubs that are targeted by the DNA damage checkpoint response to modulate chromosome
architecture and preserve genome integrity. The role of
NPCs and checkpoint kinases in maintaining genome
integrity is of great interest in view of their role in influencing chromosome replication, DNA recombination and
repair [15]. NPC abnormalities and checkpoint deficiencies are associated with aberrant chromosome dynamics
and genome instability [6,7].
The checkpoint-mediated relocalization of damaged
chromatin to NPCs influences DNA repair [8], whereas
the checkpoint kinases assist DNA synthesis across transcribed genes by releasing transcribed chromatin from
NPCs [9]. Hence, the physical proximity between chromatin and the nuclear envelope is highly regulated and, in
addition to impacting upon a variety of chromosome events
under normal conditions, such proximity also influences
the cellular response to DNA damage.
During oncogene-induced malignant transformation,
cells accumulate DNA damage due to replication stress
[1013], and the DNA damage checkpoint acts as an
Corresponding authors: Bermejo, R. (rodrigo.bermejo@usal.es); Foiani, M.
(marco.foiani@ifom-ieo-campus.it)
Keywords: nuclear envelope; checkpoint; chromatin; DNA topology; genome integrity.
*
Current address: Instituto de Biologa Funcional y Genomica (IBFG), Consejo
Superior de Investigaciones Cientficas (CSIC), Universidad de Salamanca, Spain.

anticancer barrier by suppressing genomic instability

[14]. The checkpoint-mediated control of chromatinnuclear
envelope tethering is probably crucial in an oncogenic
context in which chromosome replication must deal with
massively deregulated transcription [15]. Characterization
of the multilayered regulatory circuits and mechanisms
coupling NPCs and chromatin will be therefore instrumental in shedding light on those events leading to chromosome
fragility and on several human pathologies caused by
mutations in nuclear envelope-associated proteins. Moreover, understanding the relation between NPCs and
chromatin will help to unravel key aspects of malignant
transformation.
We review here recent evidence defining novel roles of
the DNA damage checkpoint in the control of chromosome
architecture and the subcellular relocalization of genomic
loci in response to genotoxic insults. We also discuss how
abnormalities in the interface between the nuclear and
chromosomal DNA may generate genomic lesions, and the
impact of nuclear envelope functional deficiencies in the
development of human pathologies, including cancer.
NPCs as DNA repair hubs
NPCs are large macromolecular structures that evolved
upon the compartmentalization of the eukaryotic cell to
mediate intracellular trafficking between the nucleus and
cytoplasm [16] (Box 1). In addition to their essential role in
nucleocytoplasmic trafficking, NPCs also serve as platforms
for different cellular processes including gene expression,
chromosome segregation, and cell differentiation [5,17]
Seminal observations emerged from yeast genetic
screens pinpointing the functional links between DNA
replication, DNA repair, and NPC components [7]. Further
work showed that DNA double-strand breaks (DSBs) associate with NPCs through a mechanism dependent on the
nucleoporin Nup84 and the action of the Slx5Slx8 SUMOtargeted ubiquitin ligase complex. DSB relocalization
probably assists repair and counteracts gross chromosomal
rearrangements [8]. Intriguingly, the peripheral relocalization of DNA breaks relies on the histone variant H2A.Z/
Htz1 [18]. Damaged chromatin relocalization at NPCs
probably represents a late step in the DSB response, which
is initiated by a Mec1/ATR-dependent process that leads to
increased chromosome mobility [19,20].

0962-8924/$ see front matter 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tcb.2012.05.007 Trends in Cell Biology, September 2012, Vol. 22, No. 9

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Box 1. NPC structure and function

NPCs have a cylindrical structure with eightfold symmetry sitting in
the pore membrane where inner and outer nuclear envelope
membranes meet. Each pore is formed by a core structure of eight
spokes composed of NPC proteins (or nucleoporins) and a central
tube that connects the cytoplasmic and nuclear compartments.
Filaments emanate from the core either to the cytoplasm, the lumen
or the nucleoplasm, the latter forming the inner nuclear basket. Core
nucleoporins form two symmetrical inner and outer rings, which
associate with the nuclear membrane through the luminal ring.
Linker nucleoporins mediate the association of the NPC core with
the FG nucleoporins, characterized by the presence of phenylalanineglycine repeats, which directly mediate nucleocytoplasmic
transport. Inner basket nucleoporins instead play essential roles in
regulating mRNA export and gene gating. Nucleus/cytoplasm
transport involves a series of highly regulated mechanisms to allow
the controlled transport of specific cargoes while impeding the
passage of nonspecific macromolecules [16]. Subcellular localization has also been evolved to regulate protein function by excluding
key factors from their targets/interactors.

Telomeres are specialized structures that protect chromosome ends and prevent their resection, thus counteracting the local generation of checkpoint signals [21].
Telomere ends are bound by Yku70/Yku80, a complex that
also associates with DSBs [22,23]. The Mlp1 and Mlp2
nucleoporins interact with Yku70 and have been proposed
to tether telomeric chromatin to the nuclear envelope [24],
although this function remains controversial [25]. The
perinuclear position of the telomeres correlates with telomeric chromatin silencing, and both are lost in mlp1 mlp2
double mutants [24,26]. Unprotected telomere ends undergo progressive erosion, thus eliciting a checkpoint response

that eventually triggers cell senescence [27,28]. Similarly

to DSBs, the association of eroded telomeres with NPCs is
checkpoint-dependent [29,30]. The integral nuclear membrane protein Mps3 [31] is required for both DSBs relocalization [8] and Yku-mediated telomere anchoring to the
nuclear membrane [32,33]. Together these observations
underpin the importance of the checkpoint-mediated regulation of NPC functions to modulate chromosome architecture in response to genotoxic insults and/or telomeric
dysfunction (Figure 1). However, further investigations are
required to define how the peripheral relocalization of
damaged chromatin assists its repair. In this respect, it
was shown that Sae2, an important factor required to
prime DSB repair by homologous recombination, undergoes autophagic degradation outside the nuclear compartment [34]. One possibility is that, by bringing DNA lesions
into the NPC microenvironment, certain repair factors
may turn over more rapidly.
Nuclear envelope-mediated control of rDNA stability
The impact of the nuclear envelope on genome integrity is
not restricted to DSB repair. The stability of ribosomal
DNA (rDNA) repeats strictly depends on the coordination
between replication and transcription of the 35S genes
[35]. Forks clashing head-on with the 35S transcription
machinery stably pause at specialized replication fork
barriers (RFBs), which require Fob1 (fork blocking protein
1), thus allowing 35S replication by codirectional forks that
emanate from replication origins firing at neighboring
repeats. FOB1-ablated cells experience DNA breaks and
unscheduled recombination events between rDNA repeats

CLIP

NPC

DSB
sTel

Tel
rDNA

Gated gene

Checkpoint response
TRENDS in Cell Biology

Figure 1. Checkpoint-mediated regulation of chromatinnuclear envelope tethering. Chromatin association to the nuclear envelope influences various chromosomal
processes. Ribosomal DNA (rDNA) repeats and telomeres (Tel) associate with the nuclear envelope through the CLIP complexes and the nuclear pore complexes (NPCs),
respectively. It is unclear whether these associations are influenced by the checkpoint response. Loss of perinuclear hooking correlates with rDNA repeat instability and
silencing defects at telomeres. The DNA damage checkpoint relocates DNA double-strand breaks (DSBs) and eroded telomeres (sTel) to the NPCs, probably to facilitate DNA
repair events. The checkpoint response counteracts the association of transcribed genes to the NPCs (gated genes) to prevent replication fork abnormalities. The checkpoint
kinases phosphorylate several components of the NPC.

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Trends in Cell Biology September 2012, Vol. 22, No. 9

[36]. Fob1 physically interacts with Tof2 and the Cohibin

(Csm1/Lrs4) complex at the RFB [37]. The Cohibin complex
interacts with the inner nuclear matrix-associated CLIP
complex, composed of Heh1/Src1 and Nur1 [37]. The interactions between Fob1, Cohibin and the CLIP complex are
required for tethering rDNA repeats to the nuclear membrane. Fob1 has also been shown to interact with a series of
other factors to anchor rDNA repeats to the nuclear
periphery [38].
Intriguingly, CLIP disruption not only releases rDNA
repeats from the nuclear envelope but also destabilizes
rDNA repeats [38]. Although the mechanisms leading to
rDNA repeat destabilization following detachment from
the nuclear periphery remain obscure, they might be dramatically influenced by the peculiar chromosomal architecture of the locus. It was suggested that CLIP acts as a
molecular clamp bringing together two rDNA repeats [39].
By associating adjacent rDNA sequences, CLIP would
stabilize chromatin loops and, at the same time, attach
them to the inner nuclear membrane. The tethering of
rDNA loops to the nuclear matrix might impose topological
constraints and thereby affect the stability of paused forks
and the transcription of rDNA genes. It is worth noting
that the lack of topological simplification in mutants in the
genes encoding DNA topoisomerase I (Top1) and II (Top2)
leads to the excision of rDNA copies as extrachromosomal
rings [40,41]. Possibly, the architecture of rDNA repeats is
influenced by topological events occurring at the base of the
cohibin-stabilized chromatin loops that counteract aberrant transitions and unscheduled recombination events.
Although it remains to be elucidated whether the checkpoint response plays any role in the architectural organization of the rDNA cluster, we note that the CILP complex

factor Src1 has been found to interact physically with the

checkpoint kinase Rad53 [42].
Checkpoint-mediated control of NPCs and impact upon
replication fork stability
Intracellular trafficking through the NPCs can be influenced by the DNA damage checkpoint to indirectly stabilize replication forks. tRNA transcription is known to
pause replication forks [43], and DNA damage checkpoint
activation represses tRNA transcription [44] and its export
by regulating the Los1 karyopherin [45], which interacts
with the Nup60 and Srp1 nucleoporins at the NPC inner
basket [46] (Figure 2). In addition, the checkpoint kinases
Mec1, Rad53 and Dun1 also regulate dNTP pools, which
are essential for fork processivity and accurate repair of
collapsed forks [47,48]. In response to genotoxic insults, the
checkpoint upregulates transcription of ribonucleotide reductase (RNR) genes, destabilizes the RNR inhibitor Sml1
[49,50], and promotes RNR catalytic subcomplex (Rnr2/
Rnr4) subcellular relocalization through the action of
Wtm1 and Wtm2 [51]. Rnr2/4 is nuclear and its translocation to the cytoplasm is regulated at the NPC through
Wtm1 and Wtm2, which act as nuclear anchors in the
absence of DNA damage [52] (Figure 2).
The checkpoint-mediated regulation of NPCs also
impacts upon transcription-dependent chromosome architecture. Following transcriptional initiation, mRNA genes
rapidly localize to NPCs [5356]. The perinuclear association of genes persists for extended periods of time [53]. This
phenomenon, known as gene gating [57] (Figures 1 and 2),
seems to occur at every transcribed locus [54]. Gene gating
might enhance gene expression by bringing nascent mRNA
into the vicinity of NPCs [56]. The THO/TREX and TREX-2

tRNA
RNR
Sml1
dNTPs

CLIP

dNTPs
STOP

NPC

STOP

RNPIII

STOP

rDNA
REP

RNPII
Gated gene

Checkpoint response
TRENDS in Cell Biology

Figure 2. The checkpoint influences chromosome replication by modulating events at nuclear pore complexes (NPCs). In response to genotoxic insults, the checkpoint
inhibits RNA polymerase III (RNAPIII)-mediated tRNA transcription as well as tRNA export to the cytoplasm, probably to remove the impediments represented by the bulky
transcriptional machinery. Upon checkpoint activation, ribonucleotide reductase (RNR) subunits constitutively retained in the nucleus are relocated to the cytoplasm where
they can form an active complex with the Rnr1 subunit. Full RNR activation is achieved by degradation of its inhibitor, Sml1, through a process mediated by the Dun1
checkpoint kinase. RNAPII-transcribed loci associate with NPCs and are organized in a complex architecture that hinders replication fork progression. Checkpoint kinases
phosphorylate key nucleoporins, including Mlp1, to release gated genes from the nuclear envelope. Replication forks can then proceed.

467

Review
complexes, which are involved in transcriptional elongation, cotranscriptional processing and mRNA export,
bridge transcribed chromatin and the inner basket of
the NPC [53,55]. Gene gating-mediating factors also include particular inner basket nucleoporins such as Nup1
and Mlp1 [53,58], as well as the histone variant Htz1 [59].
Because Htz1 is also required for both the establishment of
transcriptional memory [59] and the relocalization of DSBs
to NPCs [18], it is possible that Htz1 facilitates the formation of common chromatin architectural determinants specialized in mediating chromosome interaction with NPCs.
In addition to assisting mRNA expression, gene gating
has a profound impact upon the stability of replication
forks (reviewed in [15]). During S phase, topological stress
is generated at replication forks (Box 2) [60,61], and in
particular when they clash with transcription units [15].
Unresolved positive supercoiling can lead to fork reversal
[60,62] and chromosome fragility [63], whereas negative
supercoiling facilitates the formation of R loops [64,65].
Fork reversal and chromosome fragility are typical features of checkpoint-deficient cells [6668], whereas R loops
accumulate in gene gating mutants [69,70]. Association of
transcribed chromatin to NPCs establishes numerous
interactions between the chromosomes and the nuclear
membrane. These genome adhesion points modulate the
way the topological stress generated by DNA replication
diffuses along the chromosomes. Sites where the rotation of
DNA helical strands around each other is prevented by the
physical association to fixed nuclear structures (such as the
nuclear envelope) behave as topological barriers [62,71].
The ablation of the gene gating-mediating THO/TREX and
TREX-2 components, or of key nucleoporins, rescues fork
reversal in checkpoint mutants [9], suggesting that gated
genes might indeed behave as topological barriers facilitating the accumulation of positive supercoiling. Several
factors involved in gene gating, including Mlp1, are targeted by the checkpoint kinases [72,73] and, following
checkpoint activation, transcribed chromatin is released
from the nuclear periphery to facilitate fork progression
across mRNA genes [9] (Figure 2). Hence, the checkpoint
response may control the topological architecture of chromosomes by modulating the association of transcribed

Box 2. Topological stress accumulation at replication forks

Topological stress is generated at replication forks [60,61]. DNA
unwinding by replicative DNA helicases reduces the number of
crosses between the parental DNA strands. This generates a
compensatory increase in the linkage of the unreplicated portions
of the DNA helix that can be accommodated as positive supercoiling
or diffuse behind the fork in the form of precatenanes. Positive
supercoiling imposes a torsional stress that tends to reanneal
parental strands, thus counteracting the helicase function at the
forks [63]. Conversely, precatenanes establish physical links
between sister chromatids and can give rise to DNA breaks upon
chromosome segregation in mitosis [99]. In eukaryotic cells,
topological stress is counteracted by the action of DNA topoisomerases, which create transient nicks in DNA strands to change the
topological state. Type IB (Top1) and IIA (Top2) topoisomerases
move with replication forks and cooperate in removing positive
supercoiling [61]. Precatenanes instead can only be resolved by the
action of type II enzymes that mediate the passage of entire
duplexes through each other.
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Trends in Cell Biology September 2012, Vol. 22, No. 9

chromatin to the nuclear envelope. Whether the checkpoint-mediated inhibition of gene gating has a causative
role in increasing chromosome mobility following DSB
formation [19,20] remains to be elucidated.
Even though some components of the THO/TREX
(SAC3/GANP), SAGA complex and nuclear basket nucleoporins are conserved up to humans [74], gene gating has
not been described so far in metazoa. Intriguingly, in
human cells, particular nucleoporins can be released from
NPCs and bind chromatin to modulate transcription [75].
In theory, released nucleoporin complexes could hinder
DNA strand rotation similar to the gene gating apparatus,
but this hypothesis has not yet been experimentally explored. Future work would be required to establish whether nucleoporins also impose topological barriers in
mammalian cells. Nevertheless, cotranscriptional processes, and particularly splicing, may very well impose topological barriers equivalent to those generated at gated
genes in yeast cells. For instance, during mRNA splicing,
loops protruding intronic sequences are stabilized by splicesosomes. The formation of large molecular complexes,
including intronic RNA loops and splicing factors, would
limit DNA strand rotation and generate topological barriers. Intriguingly, the activity of mammalian DNA topoisomerase I is influenced by splicing [76]. Moreover human
DNA topoisomerase I promotes the stability of replication
fork progression at transcribed genes by inhibiting the
splicing factor ASF/SF2 [77], thus simplifying the topological context at sites where forks clash with the splicing
machinery. Importantly, human genes involved in splicing
and mRNA processing are targeted by the ATR and ATM
checkpoint kinases [78] and score as the most abundant
classes in screens performed in human cells to identify
factors preventing DNA break formation [79]. A challenge
for future studies will be to understand whether in mammals the nuclear envelope influences events at replication
forks as they encounter genes that undergo cotranscriptional splicing, and whether the checkpoint response plays
any role in preventing the local accumulation of topological
impediments.
Nuclear envelope deficiencies and human diseases
In mammals, nuclear envelope-associated genomic instability is mostly linked to malfunctioning of Lamins A/C [80]
(Table 1). Intriguingly, lamins do not seem to be required
for cell proliferation [81] but instead contribute to maintaining chromatin structure and assisting gene expression
[82]. Recent findings reporting in vivo alterations in many
nucleoporins in human malignancies (Table 2) have increased interest in addressing the contribution of nucleoporins to preventing genome instability in mammals [83].
These studies have shed light on human pathologies that
can arise due to the improper functioning of the NPC. We
discuss below some of the key observations in metazoans
linking nucleoporins with genome instability.
Recently, two studies highlighted the role of NUP153
(located within the NPC basket) in the maintenance of
genome integrity. NUP153 was identified in a study using
siRNA-based screens aimed at unmasking novel players in
g-ray (IR)-induced DNA damage response (DDR) foci formation [84]. Depletion of Nup153 in HeLa and U2OS cells

Review

Trends in Cell Biology September 2012, Vol. 22, No. 9

Table 1. Nuclear envelope-related diseases

Protein
Emerin
MAN1
Nesprin-1
TorsinA
LBR
(Lamin B receptor)
Lamin B1

Lamin B2
Prelamin A
Lamin A

LAP2
Nesprin 1
Nesprin 2

Table 2. Nucleoporin-related diseases

Disease
Cardiomyopathy with muscular
dystrophy, ovarian cancer
Sclerosing bone dysplasias
Cerebellar ataxia
DYT1 dystonia
PelgerHuet anomaly
Greenberg skeletal dysplasia
Adult-onset autosomal dominant
leukodystrophy, hepatocellular
carcinoma, and prostate cancer
Acquired partial lipodystrophy
Dermopathy and progeroid disorders
HutchinsonGilford progeria syndrome
Atypical Werner syndrome
Muscular dystrophy
Cardiomyopathy
CharcotMarieTooth disease
Familial partial lipodystrophy
Colorectal cancer
Prostate cancer
Ovarian cancer
Colon cancer
B cell lymphoma
Malignant lymphocytes
Invasive ovarian cancer
Colorectal cancer
Breast cancer

Refs
[100]

Protein
TPR

[101]
[102]
[103]
[104]

Aladin
Nup358/RanBP2

[105]

[106]
[107]
[108]
[109]
[110]
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[121]

resulted in impaired nuclear translocation of 53BP1, a

mediator of the DNA damage checkpoint. The reduction
in nuclear 53BP1 resulted in delayed DSB repair and
impaired cell survival. Of note, some nucleoporins, including Nup153 [85], were found among other nuclear envelope-associated proteins as putative substrates of the Chk1
checkpoint kinase in a peptide screen aimed at identifying
novel factors involved in the DNA damage response (DDR)
pathway (Figure 3). These observations suggest an unexplored direct role of nucleoporins in the protection of
genome integrity. Another study [86] reported similar

Nup155
Nup98

Nup214

Nup62

Nup88

Nup133

Disease
Gastric cancer and papillary
thyroid carcinoma
Colorectal cancer
Osteosarcoma
Triple A syndrome
Acute necrotizing encephalopathy
Inflammatory myofibroblastic tumor
Atrial fibrillation
Acute myeloid leukemia
Hematologic malignancies
T cell acute lymphoblastic leukemia
T cell acute lymphoblastic leukemia
Acute myeloid leukemia
Hematopoietic malignancies
Breast cancer
Primary biliary cirrhosis
Autosomal recessive infantile bilateral
striatal necrosis
Ovarian cancer
Hepatocellular carcinoma and colorectal
cancer
Breast, colorectal, and endometrial cancer
Colorectal cancer
Breast cancer

Refs
[122]
[122]
[97]
[87]
[123]
[124]
[125]
[126]
[127]
[128]
[129]
[130]
[122]
[121]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[120]

defects in cell survival following induction of DSBs in

Nup153-depleted cells.
The AAAS gene encodes the ALADIN protein and point
mutations in this gene are associated with a rare autosomal recessive disorder termed triple-A (AAA) syndrome.
ALADIN is primarily located at the cytoplasmic side of the
NPCs and mutations in the AAAS gene produce a defective
ALADIN protein that cannot be targeted to the NPC [87].
Interestingly, NPCs in cells from AAA syndrome patients
appear morphologically normal [87]; however, it was proposed that, because triple A syndrome is mainly caused by
impaired translocation of ALADIN at the NPCs, ALADIN
might play a role in either the formation of macromolecular
complexes at the nuclear pore or in nucleocytoplasmic

Nuclear envelope associated

Vigil

in

iate

lear

Nuc

ore

oc
ass

NUP2

Lamin

SRP1

RIF1

KAP95

NUP1

Chk1

NUP60
MLP1

NUP
98
TPR

RAD53

NUP
153

RAN

BP2

Nuclear pore associated

TRENDS in Cell Biology

Figure 3. The checkpoint targets key components of the nuclear envelope. Key nucleoporins and nuclear pore complex (NPC)-associated factors are regulated by the
checkpoint kinases both in yeast (Rad53) and mammalian cells (Chk1). Proteins indicated in blue are Rad53 substrates [72], in green are physical interactors. All proteins
connected to Chk1 are substrates identified by phosphoproteomic screens [85]. Factors represented in green are components of nuclear pore complex, whereas nuclear
envelope proteins are represented in magenta.

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Trends in Cell Biology September 2012, Vol. 22, No. 9

TPR/Mlp1

TPR/Mlp1
Mad1

Mad2
TPR/Mlp1

Telomere
Kinetochores

Gated gene

TRENDS in Cell Biology

Figure 4. TPR/Mlp1 as a key mediator of chromosome architecture. The myosin-like protein TPR/Mlp1 associates with the nuclear pore complex (NPC) inner nuclear basket,
and modulates different cellular processes including telomere physiology, gene gating, and the spindle assembly checkpoint (SAC). The SAC factors Mad1 and Mad2
associate with NPCs in a TPR-dependent manner and TPR is required for proper SAC surveillance and balanced chromosome segregation to daughter cells following
microtubulekinetochore attachment.

shuttling of key factors [88]. The dissection of the molecular mechanisms leading to AAA syndrome was hampered
when the ALADIN deficient mice did not show triple A-like
symptoms [89], suggesting that the ALADIN role might be
redundant. However, studies using the ALADIN-I482S
mutation in HeLa and I482S fibroblast cell lines showed
impairment in nuclear import of particular proteins and
increased sensitivity to oxidative stress [90].
ELYS (embryonic large molecule derived from yolk sac)
has been shown to be essential for NPC assembly in
Xenopus extracts and human cell lines [91]. ELYS was
also implicated in mediating proper cytokinesis. Later,
ELYS was found to link DNA replication licensing and
NPC assembly in Xenopus [92]. Knockout of ELYS is
embryonic lethal [93]. Studies in mouse intestinal epithelial progenitor cells using a conditional Elys knockout
mouse model [94] showed an increase in gH2AX and p53
levels with an activated DNA damage response when
compared to wild-type cells. The authors inferred from
their observations that murine ELYS, unlike its human/
zebrafish counterpart [91,95], does not have any impact
upon NPC assembly but regulates genomic instability.
Another integral component of the nuclear pore basket
is TPR (Mlp1 in yeast cells), which is specifically involved
in mRNA export, telomere metabolism, and nuclear envelope architecture [96] and was originally found in a human
osteogenic sarcoma cell line [97]. TPR has also been implicated in mitotic spindle checkpoint control where it is
required for MAD1 and MAD2 activation. In fact, suppression of TPR protein levels resulted in a defective spindle
checkpoint. The authors also suggested that the chromosomal rearrangements in the TPR gene in particular cancers might lead to genomic instability [98]. Moreover, TPR
is targeted by ATM/ATR-dependent phosphorylation
events following g-irradiation [78] (Figure 3). Depletion
of TPR resulted in defective intra S-phase and G2/M
checkpoints, suggesting a key role for TPR in influencing
genome integrity (Figure 4).
In addition, an siRNA screen identifying genes involved
in the regulation of genomic integrity revealed several
nuclear pore proteins [79]. In another approach [78], a
470

proteomic screen identified novel substrates for ATM

and ATR upon genotoxic stress. These findings exposed
nuclear pore proteins as possible targets of the checkpoint
response. Although their precise roles within the DDR
machinery need to be elucidated experimentally, a direct
role for nucleoporins in preserving genome stability is
highly anticipated.
Concluding remarks
We are only now starting to unravel the interplay between the nuclear envelope, the chromatin and the DNA
damage checkpoint and its influence in preserving genome integrity. Future studies should contribute to elucidation of the checkpoint-mediated mechanisms and the
key checkpoint targets that modulate chromosome architecture, influence DNA topological transitions, and facilitate DNA repair. It will be a challenge in the future to
integrate mechanistic studies and genomic observations
and to address whether the mechanistic details observed
in the various model systems have been evolutionary
conserved in human cells. This might provide a framework to understand key aspects of genome instability
and malignant transformation.
Acknowledgments
We thank Giordano Liberi, Dana Branzei and all members of our
laboratories for discussions. M.F. was supported by grants from
Fondazione Italiana per la Ricerca del Cancro (FIRC), Associazione
Italiana per la Ricerca sul Cancro (AIRC), Associazione per la Ricerca
Internazionale sul Cancro [Association for International Cancer Research
(AICR)], Telethon-Italy, European Commission (EC) GENICA project and
Italian Ministry of Health. R.B. was supported by the Spanish Ministry of
Science and Innovation (RYC-2010-07131 and BFU2011-24909) and the
EC Framework Program 7 (under grant agreement no 293770). A.K. was
supported by long-term European Molecular Biology Organization and
Marie Curie Intra-European postdoctoral fellowships (under grant
agreement No 274093). The IBFG acknowledges support from the
Ramon Areces Foundation.

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