Published OnlineFirst October 28, 2013; DOI: 10.1158/1078-0432.CCR-12-3667
Clinical
Cancer
Research
Molecular Pathways
Molecular Pathways: Transcription Factories and
Chromosomal Translocations
Cameron S. Osborne
Abstract
The mammalian nucleus is a highly complex structure that carries out a diverse range of functions such as
DNA replication, cell division, RNA processing, and nuclear export/import. Many of these activities occur at
discrete subcompartments that intersect with specific regions of the genome. Over the past few decades,
evidence has accumulated to suggest that RNA transcription also occurs in specialized sites, called
transcription factories, that may influence how the genome is organized. There may be certain efficiency
benefits to cluster transcriptional activity in this way. However, the clustering of genes at transcription
factories may have consequences for genome stability, and increase the susceptibility to recurrent chromosomal translocations that lead to cancer. The relationships between genome organization, transcription,
and chromosomal translocation formation will have important implications in understanding the causes of
therapy-related cancers. Clin Cancer Res; 20(2); 1–5. 2013 AACR.
Background
Transcription is perhaps the most fundamental process
that occurs within the nucleus. It has been suggested that
three quarters of the genome is associated with some degree
of transcriptional activity (1). Like many other nuclear
processes, transcription seems to be spatially segregated. The
nucleolus has long been considered a paradigm of nuclear
substructures. It sequesters the nucleolar organizer regions,
which are located across several chromosomes, to enable a
centralized transcription of the ribosomal genes by RNA
polymerase (RNAP) I. It is not as generally well recognized,
yet transcription by the other two forms of polymerase has
also been suggested to be compartmentalized; RNAP II,
which transcribed protein-coding genes, and RNAP III,
which transcribed transfer RNA genes, seem to be concentrated separately at discrete, immobile sites called transcription factories, in which all transcription seems to occur (Fig.
1A; refs. 2–5). However, the existence of these structures has
not been universally accepted, as they cannot be visualized
directly by light microscopy. Questions have been directed at
nonphysiologic conditions in which they have been
observed, and whether they represent a stable structure,
rather than a transient burst of transcriptional activity (6,
7). Live-cell imaging experiments have been used to address
these issues. The first attempts sought to observe the dynamics of a GFP-tagged RNAP II holocomplex by fluorescence
Author's Affiliation: Nuclear Dynamics Programme, The Babraham Institute, Cambridge, United Kingdom
Corresponding Author: Cameron S. Osborne, The Babraham Institute,
Cambridge CB22 3AT, United Kingdom. Phone: +44-1223-496474, Fax:
+44-1223-496022; E-mail: [email protected]
doi: 10.1158/1078-0432.CCR-12-3667
2013 American Association for Cancer Research.
microscopy (8). Although individual factories were not
observed directly due to an overwhelming excess of freelydiffusing RNAP II that obscure localized concentrations,
photobleaching experiments suggested the existence of a
relatively immobile subpopulation, consistent with the transcription factory model. Curiously, new studies using superresolution photoactivation localization microscopy of GFPlabeled RNAP II have suggested that RNAP II clusters form
only transiently, and do not seem to be a part of a stable
structure (9). However, others have fluorescently tagged
CDK9, a kinase that associates specifically with the elongating RNAP II complex, and observed the existence of highly
spatially and temporally stable, RNAP II-associated foci, with
similar numbers, size, and distribution of transcription foci
as have been detected in fixed cells (10). This suggests that
although particular components may have variable residency times and turnovers, there do seem to be established,
stable compartments in which RNAP II transcription occurs.
Typically, hundreds of RNAP II-type transcription factories are distributed fairly evenly across the nucleus, each
measuring between 40 and 200 nm in diameter (Fig. 1A;
refs. 11, 12). The protein components of factories have been
characterized by Melnik and colleagues, who used careful
purification methods to isolate Megadalton-sized complexes that contained either RNAP I, II, or III (13). Complexes were analyzed by mass spectrometry, and hundreds
of associated factors were identified, including multiple
factors associated with transcription and RNA processing.
Interestingly, although many identified factors were found
to be in common between the complexes of the three RNAP
forms, there were some differences in their composition.
Moreover, transcription of the RNAP I, II, and III genes was
associated specifically with their corresponding complex,
which highlights a distinct location and function for factories of each polymerase subtype.
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Osborne
A
B
Nontranscribed
gene
Transcribed
genes at
transcription
factory
?
Faithful DNA
damage repair
Concurrent DNA
double-strand break
formation in two
transcribing genes
Aberrent DNA
damage repair
Transcription factory
RNAP II
Transcription factors
DNA Repair factors
Germline
arrangement
Chromosomal
translocation
© 2013 American Association for Cancer Research
Figure 1. A, genes (green and orange) cotranscribe at a shared transcription factory (light blue). Genes that are positioned away from the factory (red) are not
actively transcribed. Factories have localized concentrations of transcription factors (colored spots) and polymerase (pink), as well as DNA repair factors
(brown). Differences in relative concentrations of transcription factors may influence, and be influenced by the genes that are present. B, if simultaneous
double-strand breaks occur in juxtaposed genes, the DNA damage can either be repaired faithfully (solid arrows) or in rare events abnormally, resulting in a
chromosomal translocation (dashed arrows).
The positional stability of the transcription factory structure seen by some live-cell imaging studies would suggest it
might be tethered to some nuclear scaffold, rather than exist
as a free-floating aggregate of transcription. In support of
this, Mitchell and Fraser found that factory numbers and
distribution remain constant following global transcriptional arrest by heat shock (14). Furthermore, depletion of
lamin B1, which forms an internal lattice through the
nucleoplasm (15), leads to a gross disruption of transcriptional architecture (16, 17). Interestingly, lamins and other
structural components such as nucleophosmin were identified in the transcription factory proteomics studies, which
reinforces the likelihood that factories are associated with a
nuclear scaffold (13).
With evidence of transcriptional activity localized at the
factories, one would predict that active genes are associated
with them. Indeed RNA immuno-FISH experiments, used to
measure the association of actively transcribing alleles with
factories, suggest that effectively all transcription occurs at
the factory (12, 18, 19). However, it does not seem that all
genes are docked at factories. Permanently inactive genes are
positioned away from the factories, and active genes that
undergo stochastic cycles of transcription seem to shuttle to
and from the factory in concordance with their activity
(12, 20). Importantly, factories seem to act as hubs of
activity, in which multiple genes are capable of transcribing
concurrently; however, it is not clear exactly how many
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Clin Cancer Res; 20(2) January 15, 2014
genes can be accommodated at any given time. Coassociation is not restricted to genes that are clustered together at
the same genomic locus. Genes that are widely separated,
either on the same or different chromosomes, are commonly found to transcribe together at the same factory
(12, 19, 20). Remarkably, the choice of which genes coassociate is not haphazard, because some gene pairs are found
to cooccupy a factory more often than others. It has been
suggested that these preferences are a reflection of gene
regulation by shared sets of transcription factors; a high
frequency of clustering has been detected for genes regulated by both Klf1 and TNF-a (19, 21). It also seems that
promoter identity directs the coassociation preference (22).
It is not clear how specialization of factories is achieved, but
preferences may be established through self-organization
principles, driven by the sharing of specific transcription
factors (23). Regardless, the web of preferences of gene
coassociations at factories, and motor forces generated by
the polymerase complexes opens the possibility that transcription exerts a major influence on the genome, and
accounts for cell-type–specific differences in organization.
Proximity, transcription, and chromosomal
translocations
The prevalence of cancers that originate from a specific
chromosomal translocation is influenced heavily by the
susceptibility of the rearranging regions to DNA damage,
Clinical Cancer Research
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Published OnlineFirst October 28, 2013; DOI: 10.1158/1078-0432.CCR-12-3667
Nuclear Compartmentalization, Transcription, and Cancer
as well as the oncogenicity of the resulting fusion. However,
it seems that genome organization also has a role to play.
Genes that are frequently rearranged in common cancers
often occupy similar positions within the nuclei of normal
cell types, in which the translocation is likely to occur. For
example, measurement of separation between the recurrent
translocation partner genes BCR and ABL1, PML and RARA,
and MYC and IGH within normal cells revealed they are
frequently positioned within 1 to 2 mm of each other (24–
26). Although such a separation is smaller than might be
anticipated, in real terms, these distances are still too great to
accommodate a genetic exchange. Ultimately, a considerably more intimate juxtaposition would be required to
occur at some point for a rearrangement to take place.
There has been some debate whether juxtaposition of
alleles destined to rearrange occurs before or after the
generation of DNA damage. Aten and colleagues observed
that multiple, widely separated double-strand DNA breaks
coalesce following their generation by a particle bombardment (27). Moreover, they found that DNA damage,
induced by g irradiation, augments the mobility of the
damaged regions, which supports a "break before juxtaposition" model of DNA repair (28). However, Soutoglou and
colleagues have observed that the broken ends of a fluorescently tagged, enzyme-induced double-strand break do
not separate, nor does the break dramatically change its
nuclear position (29). Furthermore, live-cell imaging of a
translocation suggested that most rearrangements occur
from alleles that were prepositioned in relative proximity
(30). In the face of these discrepancies, there may be
fundamental differences in the specific effects caused by
different sources of DNA damage (e.g., radiation-induced
vs. enzymatic cleavage). Also, the activities in which the
DNA is engaged at the time that damage is incurred may also
be significant.
The coassociation of genes at a shared transcription
factory may represent one circumstance during which a
chromosomal translocation may occur (Fig. 1B). Not only
would the discrete dimensions of the factory provide an
intimate setting in which the genes could undergo a genetic
exchange, their transcriptional activity while engaged with
the factory may also contribute to chromosomal rearrangements. The process of transcription generates considerable
force that is translated into DNA supercoiling, as the template is reeled through the RNAP machinery (31, 32). Such
torsional stress can be relieved by topoisomerases, which
relax the twist by generating transient nicks and cuts to the
DNA, followed by repair. In fact, evidence suggests that
topoisomerase-induced double-stranded breaks are necessary for full transcriptional output of some genes, indicating
that programmed DNA break and repair is an integral part
of the transcription process (33). Clearly, a heightened risk
of DNA double-strand breaks, whereas transcribing genes
are engaged at a shared factory would present inherent
dangers of chromosomal translocations that must be kept
in check. Significantly Ku70/80, a protein complex that
senses the formation of double-strand DNA breaks to
initiate repair, is highly enriched within transcription fac-
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tories (34). It suggests that the DNA repair machinery is
present to monitor tightly and control the repair process of
both regulated and aberrantly generated DNA breaks, and
thereby minimizes the occurrence of misrepair between
coassociating genes.
If chromosomal translocations do occur regularly within
the context of a transcription factory, one might predict that
the frequency at which two genes are likely to coassociate
would influence their propensity to undergo rearrangements. Indeed, RNA FISH analysis showed that the Myc
and Igh genes, the most common translocation partners in
mouse plasmacytoma and human Burkitt lymphoma, are
transcribed at a shared transcription factory at higher frequencies than are Myc and Igk or Myc and Igl, which account
for a smaller proportion of translocations in these diseases
(20). Similarly, transcription of the human protooncogene
MLL has been demonstrated to coassociate with its common translocation partner genes more often than rarer ones
(35). These correlations of gene coassociation at factories
with prevalence in cancer are highly suggestive. However,
the magnitude of its influence on cancer rates in relation to
gene mutation rates and oncogenicity of specific rearrangements is still unclear.
Recently, new genome-wide methodologies have been
applied to tease apart the contributions of these influences.
The laboratories of Alt and Nussenzweig/Casellas each have
developed new assays to capture the repertoire of genomic
regions with which the protooncogenes Igh and Myc are
capable of rearranging (36, 37). By inserting an exogenous
nuclease recognition site into these genes, they were able to
augment their translocation rates. Double-strand DNA
breaks were induced and the cells were allowed to undergo
repair only briefly, to remove selective pressures against
unfavorable rearrangements. Sequencing of the rearrangements identified the "translocatome" of Myc and Igh and
showed that the distribution of translocated partners is
biased highly toward regions on the same chromosome as
the nuclease recognition sequence, and indeed very close to
its integration site. This strong cis effect emphasizes that a
preexisting spatial proximity is a major determinant of translocation frequency. Other recombination sites were found
across the genome at lower densities. When the nucleasemediated breaks were generated in the presence of activationinduced cytidine deaminase (AID), an enzyme that induces
class switch recombination and somatic hypermutation of
immunoglobulin genes, and a driver of Igh–Myc translocations, a number of hotspots of recombination were observed.
Many of these sites occur at genes that are known targets of
AID action and implicated in B-cell cancers. Therefore, even
in the absence of selective pressures that favor the outgrowth
of particular rearrangements, certain translocations are preferred. Significantly, both studies demonstrated a strong
proclivity for translocation breakpoints to be positioned at
or near the transcription start sites of active genes. Similarly,
another study showed that transcriptional induction through
androgen receptor signaling of genes positioned across the
genome leads to their juxtaposition, transcription, and subsequent involvement in translocations (38). These studies
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Osborne
suggest that transcription is a major influence on translocation frequencies, which potentially could arise from the tight
proximity of genes that occupy a shared transcription factory
and/or DNA damage that occurs during transcription.
If a tight juxtaposition of genes within a transcription
factory is a common precondition of translocations, then
one would expect to find translocation partner genes in
close proximity in nonrearranged cells. The advent of
genome-wide proximity assays has enabled these questions
to be addressed (39). The Alt group, along with Zhang and
colleagues, has used Hi-C, an assay that captures a lowresolution snapshot of organization of the entire genome,
to examine how is the genome arranged in cells that contain
a nuclease recognition site, before the induction of doublestrand breaks (40). They found that translocations tend to
occur between genomic regions that were already in proximity before the rearrangement, which suggests that genomic contact is a prerequisite to recurrent translocations.
The Casellas and Nussensweig laboratories opted to use
the related 4C method to investigate the genome-wide
interactions of Myc and Igh (41). While Hi-C examines the
conformation of the entire genome, 4C is a semiquantitative genome proximity assay that focuses all the sequencing
depth on a single locus and, therefore, can provide a high
resolution of interactions. The repertoire of genomic
regions with which Myc and Igh associate in nonrearranged
B cells was compared with the translocatome profiles from
their earlier study. Intriguingly, they found that prebreak
contacts match the locations of AID-independent translocations but not AID-dependent translocation hotspots,
suggesting that for these sites, it has damage susceptibility
and not initial proximity that drives translocation frequency. However, 4C analysis by the Skok group of the Igh gene
came to the opposite conclusion; they found that a very
strong correlation exists between the genes that coassociate
with Igh in normal cells and those that have a predisposition
to translocate (42). The differences are being hotly debated
and largely relate to how the bioinformatics analyses have
been carried out (43, 44). Input from other bioinformaticians with expertize in genome organization and handling
such datasets would be highly beneficial to help resolve
these differences of interpretation.
Clinical–translational advances
Clearly, there remain some controversies surrounding
how the spatial organization of transcription ultimately
impacts the prevalence of cancers that occurs from result
from specific chromosomal translocations. However, it is
worthwhile to ponder its potential ramifications to heightened cancer risks and treatments. In particular, therapyrelated second cancers account for a disturbingly large
proportion of new cancer diagnoses (45). In the context
of intimate juxtaposition of cotranscribing genes at shared
transcription factories, DNA damage incurred through anticancer therapies such as topoisomerase inhibitors could
have profound implications to the risk of translocation,
especially considering that topoisomerase cleavage sites are
frequently associated with recombination hotspots in protooncogenes (46).
Yet, it is unclear how this information could be translated
to improved anticancer therapies. Although blocking juxtaposition of genes likely to rearrange, perhaps by suppressing their transcription, may suppress specific translocations, the feasibility and wisdom of such an approach is
debatable. A more realistic goal may be to develop more
focused anticancer drugs that can minimize deleterious
effects in cancer genes (47). Nevertheless, understanding
the underlying principles through which chromosomal
translocations occur, and the impact of genotoxic drug
action on transcribing genes are prudent considerations in
devising safer, more effective anticancer therapies.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: C.S. Osborne
Writing, review, and/or revision of the manuscript: C.S. Osborne
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.S. Osborne
Grant Support
This work was supported by Leukaemia and Lymphoma Research (UK)
Bennett Fellowship (to C.S. Osborne).
Received August 30, 2013; revised September 29, 2013; accepted October
10, 2013; published OnlineFirst October 28, 2013.
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Published OnlineFirst October 28, 2013; DOI: 10.1158/1078-0432.CCR-12-3667
Molecular Pathways: Transcription Factories and
Chromosomal Translocations
Cameron S. Osborne
Clin Cancer Res Published OnlineFirst October 28, 2013.
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