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EMBO reports 5, 3, 256–261 (2004)
doi:10.1038/sj.embor.7400101
A topological view of the replicon
Jorge B. Schvartzman1 & Andrzej Stasiak2
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1 Departamento de
Biología Celular y del Desarrollo, Centro de Investigaciones
Biológicas (CSIC), Ramiro de Maeztu 9, 28040
Madrid, Spain
2 Laboratoire d'Analyse
Ultrastructurale, Bâtiment de Biologie, Université de
Lausanne, CH-1015 Lausanne-Dorigny,
Switzerland
To whom correspondence should be addressed
Jorge B. Schvartzman Tel:+34 91 837 3112; Fax: +34 91 536 0432;
schvartzman@cib.csic.es
Andrzej Stasiak Tel: +41 21 692 4282; Fax: +41 21 692 4105;
andrzej.stasiak@lau.unil.ch
Received 21 November 2003; Accepted 23 January 2004.
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Abstract
The replication of circular DNA faces topological obstacles that need
to be overcome to allow the complete duplication and separation of newly
replicated molecules. Small bacterial plasmids provide a perfect model system
to study the interplay between DNA helicases, polymerases, topoisomerases and
the overall architecture of partially replicated molecules. Recent studies have
shown that partially replicated circular molecules have an amazing ability to
form various types of structures (supercoils, precatenanes, knots and
catenanes) that help to accommodate the dynamic interplay between duplex
unwinding at the replication fork and DNA unlinking by topoisomerases.
EMBO reports 5, 3, 256–261 (2004)
doi:10.1038/sj.embor.7400101
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Introduction
The replicon model was the first attempt to explain how DNA
replication is regulated in bacteria (Jacob et al,
1963). Originally formulated on the basis of observations made in
Escherichia coli, it was later extended to plasmids, phages and the
chromosomes of all prokaryotes and eukaryotes. Forty years later, the key
aspects of the replicon model still hold true and during this time it has
inspired numerous significant discoveries (Jacob,
1993; Nordstrom, 2003). Briefly, the
model developed the theme of the units of replication, which the authors called
replicons. The regulation of DNA replication was claimed to involve at least
two elements: a specific protein, the initiator, and a target DNA sequence, the
replicator, nowadays known as the 'origin of replication'. Just a couple of
years after François Jacob, Sydney Brenner and François Cuzin
launched the replicon model at a meeting in Cold Spring Harbor (Jacob et al, 1963), Gerome Vinograd and co-workers
found that the circular genome of the polyoma virus is supercoiled (Vinograd et al, 1965). This observation was later
extended to virtually all circular duplex DNA (Cozzarelli,
1980). Supercoiling, which literally means coiling of a coil, is a
topological property of DNA molecules in which the double helix twists around
its own axis in three-dimensional space (Bowater,
2002). The finding that DNA is supercoiled, together with the
discovery of topoisomerases (Wang, 1971) opened a
whole new field in molecular biology: DNA topology (Wang,
2002).
The principal aim of this review is to summarize what is known about
the topological changes that take place as a replicon replicates. We focus on
small bacterial plasmids, as most of the studies that have addressed this issue
have used pBR322 and other small derivatives as a model system. It should be
noted, however, that it is not always feasible to extrapolate the observations
made on small plasmids to bacterial or eukaryotic chromosomes. Plasmids are
small topological domains that do not necessarily reflect the conditions of the
large domains of the chromosomes of prokaryotes and eukaryotes (Higgins & Vologodskii, 2004).
Primer on DNA topology and DNA topoisomerases
A DNA molecule is said to be negatively (-) supercoiled when
the linking number (the minimal number of passages needed of one strand through
another to separate them) is lower than in the relaxed circular DNA of the
corresponding size. Both in vivo (Bliska &
Cozzarelli, 1987) and in vitro (Bednar et
al, 1994), (-) supercoiled bacterial plasmids are known to
adopt a right-handed intertwined configuration in which the duplex–duplex
crossings have a (-) sign (see Fig 1A,B for an
explanation). In eukaryotic cells, (-) supercoiling is constrained by the
left-handed winding of the DNA around nucleosomes, resulting in a toroidal
winding in which duplex–duplex crossings also have a (-) sign
(Fig 2B). As shown in Fig 1A, local
strand separation by a DNA helicase in (-) supercoiled DNA molecules
initially leads to the relaxation of (-) supercoiling, whereas further
separation causes the accumulation of positive (+) supercoiling. The arising
torsional stress opposes further helicase action and topoisomerases are
required for further separation of the DNA strands.
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Figure 1
Supercoiling: its handedness and sign. (A) Negatively
supercoiled DNA (left) loses supercoiling due to local DNA unwinding mediated
by DNA helicases (shown as grey wedges) and then becomes (+) supercoiled by
further strand separation. Notice that the intertwined superhelix is
right-handed in (-) supercoiled molecules and left-handed in (+)
supercoiled ones. The sign of the duplex–duplex crossings (see panel
B) changes from (-) to (+) upon a change from negative to positive
supercoiling. (B) Topological convention of sign assignment of perceived
crossings. In a (-) crossing, one would need to turn the overlying
direction arrow clockwise to align it with the underlying direction arrow (the
rotation needs to be smaller than 180°). In a (+) crossing the required
rotation would be counterclockwise. Notice that orientation of the underlying
and overlying direction arrows at each crossing are not independent from each
other but result from assigning a consistent direction along the whole DNA
molecule analysed. To facilitate sign recognition in A and B, the
overlying and underlying direction arrows are marked in red and blue,
respectively.
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Figure 2
Topological sign and handedness of duplex–duplex intertwining
in supercoiled replication intermediates. (A) Schematic drawing of
(-) and (+) supercoiled replication intermediates (RIs). (B)
Elastic transition between toroidally wound (around core histones for example)
and intertwined form of (-) supercoiled DNA. Notice that, in the
toroidally wound form, the segments that cross in a projection run in the same
direction around a virtual torus, whereas, in the intertwined form, the
crossing segments run in opposite directions around the virtual cylinder
enclosed by the DNA. This change of relative orientation causes the topological
signs to remain the same despite a perceived change from left- to right-handed
winding of the superhelices. The mathematical convention applied in DNA
topology assigns a parallel orientation to both strands of DNA (this is
required to have a (+) linking number in B-DNA, which forms a right-handed
helix; Bates & Maxwell, 1993). For this reason,
to trace the linking number contribution of parental strands in an RI, one
needs to assign the same direction to both newly replicated duplex regions. In
(-) supercoiled DNA there is a tendency to release the torsional stress
by left-handed winding of unpaired strands or by flipping runs of alternating
purine–pyrimidine from right-handed B-DNA to the left-handed Z-DNA
(DiCapua et al, 1983). It is therefore
energetically favourable in deproteinized (-) supercoiled RIs that the
newly synthesized duplex regions are wound around each other in a left-handed
way. The opposite situation applies to (+) supercoiled RIs. The parental duplex
is indicated in blue and green, whereas nascent strands are depicted in
red.
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Topoisomerases are enzymes that interconvert different topological
states of DNA. They are divided into type I and type II enzymes, which
transiently cleave one or both strands of DNA, respectively. Type I
topoisomerases are additionally divided into two subtypes: A and B. Enzymes
belonging to the subtype A have a complex mechanism of action that involves
passage of the uncut strand through the enzyme-bridged cleavage of the other
strand. Interestingly, while acting on DNA with nicks or with single-stranded
regions, type IA topoisomerases can cleave the continuous strand and allow the
passage of a segment of duplex DNA of the same or another DNA molecule through
the cut strand. Topoisomerases of the subtype IB act by a simpler mechanism
that involves free rotation of DNA at the transient nick site (Stasiak, 2003). There are two type I topoisomerases in
E. coli that are known as topo I and III and they both belong to subtype
A (Champoux, 2001). Importantly, E. coli
topo I and III are hardly active on the bulk of cellular DNA that is maintained
at physiological levels of (-) supercoiling. Non-physiologically strong
(-) supercoiling or the presence of single-stranded regions activate topo
I and III (Champoux, 2001). Type II topoisomerases
make transient double-stranded breaks and allow the passage of another duplex
across the break. They are usually ATP-dependent (Gellert
et al, 1976). There are two type II topoisomerases in E.
coli, which are known as DNA gyrase and topo IV (Champoux, 2001). As with E. coli type I
topoisomerases, gyrase and topo IV are also hardly active on the bulk of
cellular DNA and become activated by DNA relaxation in the case of gyrase and
by (+) supercoiling in the case of topo IV. It is important for energy balance
that there is no futile action of topoisomerases on the bulk of DNA through
which a gyrase, for example, would continuously use ATP to introduce (-)
supercoiling and topo I or III would relax the DNA. Topoisomerase action
therefore needs to be limited to the biological processes that involve DNA,
such as replication, transcription, recombination and repair during which DNA
topology needs to be modified.
Tug-of-war between (-) and (+) supercoiling
To initiate their replication, bacterial plasmids must be (-)
supercoiled as this facilitates strand separation at the origin of replication
(Fig 1A; Funnell et al,
1987; Marians et al, 1986). Once
initiation has been accomplished, elongation proceeds by means of a complex
ensemble of enzymes known as the replisome. The current view is that during
replication, DNA passes through a stationary replisome. In front of this
replisome, a hexameric DNA helicase separates the parental strands that are to
be used as templates. This strand separation leads to overwinding (positive
supercoiling) of the duplex ahead of the fork (Fig 1A;
Alexandrov et al, 1999; Peter et al, 1998; Ullsperger
et al, 1995). However, (-) supercoiling is important for
the opening of the DNA double helix (Crisona et al,
2000; Kanaar & Cozzarelli, 1992).
How then do replication intermediates (RIs) manage to remain (-)
supercoiled as the fork advances? The first clue to answer this question came
with the discovery of DNA gyrase (Gellert et al,
1976). It is thought that the continuous action of gyrase on the
unreplicated portion of replicating plasmids decreases the linking number of
the parental duplex (Alexandrov et al, 1999;
Peter et al, 1998; Ullsperger et al, 1995). In this way, gyrase helps
to compensate for the overwinding of the duplex as the fork advances. The rate
of unlinking by gyrase, however, is slow and might be insufficient to sustain
the rate of fork movement in E. coli (Peter et
al, 1998). Furthermore, DNA gyrase can actively cause unlinking
only when acting on the unreplicated portion of replicating plasmids (Gellert et al, 1976; Kampranis
et al, 1999). At early stages of replication, when the
unreplicating portion is sufficiently long, several gyrase molecules could work
in parallel to sustain a high speed of unlinking. As the length of the
unreplicated portion shrinks, however, there is less space for gyrase to act.
Each gyrase molecule needs around 150 base pairs to bind to DNA (Bates & Maxwell, 1989), and so overwinding caused by the
progressing fork may eventually accumulate. This potential problem was first
recognized by James Champoux and Michael Been (Champoux
& Been, 1980), who realized that this gyrase deficit would
eventually lead to the accumulation of (+) supercoiling at later stages of the
replication process. To solve this dilemma, they proposed that supercoiling
might diffuse throughout the replication fork and redistribute both ahead of
and behind the fork. In this model, the other type II topoisomerase, topo IV,
which is the main decatenase in E. coli (Zechiedrich
& Cozzarelli, 1995; Zechiedrich et al,
1997), assists gyrase to compensate for the overwinding that
accumulates as the fork advances. Brian Peter and co-workers (Peter et al, 1998) used electron microscopy to
confirm the diffusion of supercoiling across the fork in an in vitro
assay that yielded partially replicated plasmids containing stalled forks. They
called the intertwining of the sister duplexes in the replicated portion
"precatenanes" to distinguish them from the supercoiling in the
unreplicated portion (Figs 2A and 3B,D,E). The emerging idea was that unlinking of the parental
duplex during DNA replication is carried out by gyrase introducing (-)
supercoils ahead of the fork and topo IV removing precatenanes behind the fork.
This would explain why progression of the replication fork is impeded when both
gyrase and topo IV are mutated or inhibited (Hiasa et
al, 1994; Khodursky et al,
2000; Levine et al, 1998). It is
important to notice that for supercoiling to diffuse across the replication
fork, the sister duplexes should be able to rotate freely around each other at
the forks. Curiously, for a (-) supercoiled RI in vitro, the
parental duplex winds around itself in a right-handed manner ahead of the fork,
whereas behind the fork the sister duplexes wind in a left-handed manner
(Postow et al, 2001a). The reverse occurs
in the case of (+) supercoiled RIs (see Figs 2A and
3B,D,E). It is rather non-intuitive that the direction of
intertwining of opposing double-stranded regions changes between the
unreplicated and replicated portions of an RI that is under torsional stress.
However, it is well known that an elastic transition from toroidal to
intertwined forms of supercoiling changes the perceived handedness of
intertwining while maintaining the same topological sign (Fig
2B; Bauer et al, 1980). Similarly,
although the perceived handedness of duplex–duplex intertwining in
replicated and unreplicated portions of supercoiled RIs are different, the
topological sign of these crossings in both parts remain the same (Fig 2A).
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Figure 3
The topological cycle of a replicon. (A) Unreplicated
(-) supercoiled plasmid. (B) Twenty-five per cent replicated
(-) supercoiled RI where the parental duplex winds right-handed, whereas
the sister duplexes wind in a left-handed manner. (C) Fifty per cent
replicated RI where supercoiling is zero. (D) Seventy-five per cent
replicated (+) supercoiled RI where the parental duplex winds left-handed,
whereas the sister duplexes wind in a right-handed manner. (E)
Seventy-five per cent replicated (-) supercoiled RI where the parental
duplex winds right-handed, whereas the sister duplexes wind in a left-handed
manner. (F) One hundred per cent replicated catenane. (E')
Seventy-five per cent replicated (-) supercoiled RI bearing a knotted
replication bubble. (D') Seventy-five per cent replicated RI where
supercoiling is zero containing two branched four-way Holliday-like junctions,
called 'chicken-foot' structures. Red arrows indicate the putative most
frequent pathway. Grey arrows show alternative pathways. The parental duplex is
indicated in blue and green, whereas nascent strands are depicted in red.
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As mentioned previously, (-) supercoiling assists any process
that requires opening of the double helix (Crisona et
al, 2000; Kanaar & Cozzarelli,
1992). Moreover, it was recently shown that for partially replicated
molecules containing stalled forks, the introduction of net (+) supercoiling
in vitro leads to replication fork reversal through the formation of a
branched four-way Holliday-like junction, the so-called 'chicken-foot'
structure (Olavarrieta et al, 2002c;
Postow et al, 2001b; Sogo et al, 2002; Viguera et
al, 2000). In short, it is thought that the coordinated action of
gyrase and topo IV would allow RIs to remain (-) supercoiled throughout
the replication process. Therefore, at any given time during replication, the
degree of supercoiling would be the result of the balance between the action of
at least the three different enzymes already mentioned: DNA helicase, leading
to the accumulation of (+) supercoiling ahead of the fork; DNA gyrase, which
introduces (-) supercoiling in the unreplicated portion; and topo IV,
removing precatenanes behind the fork (Peter et al,
1998; Postow et al, 1999,
2001a).
Two-dimensional (2D) agarose gel electrophoresis of intact molecules
formed in vivo with the fork stalled at different distances from the
origin indicated that those plasmids with the fork stalled closer to the origin
are more supercoiled than those with the fork stalled at increasing distances
(Olavarrieta et al, 2002c). This
observation suggests that although RIs remain (-) supercoiled throughout
replication, they progressively relax as the fork advances. These results,
however, should be examined with caution, as they do not necessarily reflect
the situation during unimpaired DNA replication. In those plasmids containing
stalled forks, there might be an excess of (-) stress due to the
continuous action of gyrase once the fork has stalled.
Knotted bubbles as reporters of DNA topology in
vivo
As soon as DNA topoisomerases were discovered, it was realized that
DNA knots could form in living cells. Experimental evidence for knotted
molecules in vivo, however, was scarce (Liu et
al, 1981; Shishido et al,
1989; Shishido et al, 1987). It
was therefore surprising when studies of bacterial plasmids with stalled forks
revealed that such plasmids could be knotted in vivo and that they form
a characteristic 'beads-on-a-string' arrangement of DNA bands in 2D gels
(Santamaría et al, 1998,
2000; Viguera et al,
1996). The strategy used to identify these knotted bubbles involved
cleavage in the unreplicated portion of the plasmids and resulted in the
identification of knots confined within the replication bubbles. The
characterization of the handedness of these knotted replication bubbles by
electron microscopy (Sogo et al, 1999)
indicated that the partially replicated molecules were (-) supercoiled
when the knotting occurred (Postow et al,
1999).
Analyses of knotted replication bubbles in partially replicated
molecules with the fork stalled at different distances from the origin
indicated that the number and complexity of knotted replication bubbles
increases as the fork advances (Olavarrieta et al,
2002b). It could be argued that the probability of knotting increases
with bubble size. It is not that simple, however, as bubbles of the same size
show more knots in small plasmids in which the fork stalls towards the end of
replication (Olavarrieta et al, 2002c)
compared with large plasmids in which the fork stalls at the beginning of the
process (Olavarrieta et al, 2002b).
Altogether these observations suggest that the probability of knotting behind
the fork is inversely related to the precatenane's density (Fig
3B–E'). For regularly wound precatenanes, duplex–duplex
passages are unlikely to 'trap' another segment of the same molecule, whereas
this is not the case for loosely wound precatenanes (Sogo
et al, 1999).
Once replication is completed, the remaining precatenanes and
knotted replication bubbles automatically become catenanes (Fig
3F) that are eliminated by topo IV to allow segregation of the newly
made sister duplexes (Lucas et al, 2001;
Zechiedrich & Cozzarelli, 1995;
Zechiedrich et al, 1997). It should be
noted, however, that for the E. coli chromosome in vivo there
might be alternative ways to decatenate sister duplexes (Ip
et al, 2003). In any case, an increase in the number and
complexity of knotted replication bubbles would increase the number of nodes in
the catenane (the number of times each duplex winds around its sister) and this
would be expected to have deleterious effects on the segregation of freshly
replicated DNA molecules. Leticia Olavarrieta and co-workers (Olavarrieta et al, 2002a) tested this hypothesis by
comparing the number of knotted replication bubbles in plasmids in which the
transcription of a selected gene and replication occur in the same or in
opposite directions. The progression of transcription and replication in
opposite directions is expected to drive the accumulation of (+) supercoiling
between the forks as they approach each other (Brewer,
1988; Wu et al, 1988). The
migration of this (+) supercoiling behind the fork would relax the regular
intertwining of sister duplexes and lower the number of precatenanes. The
number and complexity of knotted replication bubbles is indeed significantly
higher when transcription and replication progress against each other (Olavarrieta et al, 2002a).
A zoo of replication intermediates
In summary, the current topological view of the replicon can be
summarized as follows: circular plasmids need to be (-) supercoiled to
initiate replication (Fig 3A). After initiation,
supercoiling is distributed between the unreplicated and replicated portions
(Fig 3B). RIs progressively relax as the fork advances
and towards the end of replication, they could lose all native (-)
supercoiling (Fig 3C). At later stages, they could even
acquire net (+) supercoiling (Fig 3D) that would,
however, be eliminated by the combined action of gyrase and topo IV to restore
the native (-) supercoiling (Fig 3E). Finally, once
replication is completed, all remaining precatenanes become catenanes (Fig 3F) and their decatenation by topo IV allows the two sister
duplexes to segregate freely to complete the cycle. The probability of knotting
behind the fork is inversely related to the precatenane's density. For this
reason knotted bubbles can form, in particular towards the end of replication
(Fig 3E'). The RIs bearing knotted replication bubbles
could be either (-) or (+) supercoiled. These knotted bubbles could be
unknotted by topo IV during replication or otherwise become catenanes once
replication is completed. Alternatively, the transient accumulation of (+)
supercoiling could lead to fork stalling and regression through the formation
of the 'chicken-foot' structure. These transient intermediates could be
rescued, however, by the combined action of topo IV and DNA gyrase to restore
(-) supercoiling and reverse fork regression (Fig
3D').
The topo IV decatenation paradox
It was recently found that topo IV relaxes (+) supercoils at a
20-fold faster rate than (-) supercoils (Crisona et
al, 2000). Furthermore, in vitro assays showed that topo
IV recognizes the chiral crossings imposed by the left-handed superhelix of (+)
supercoiled DNA (Charvin et al, 2003;
Stone et al, 2003; Trigueros et al, 2004). This observation unmasked a
new paradox. As previously stated (Figs 2A and
3B), for (-) supercoiled RIs in vitro, the
parental duplex winds around itself in a right-handed manner ahead of the fork,
whereas behind the fork the sister duplexes wind in a left-handed manner. If
this situation also applies in vivo, left-handed precatenanes in
(-) supercoiled RIs would be recognized and eliminated by topo IV in a
preferential manner. In such a case, topo IV action would be detrimental, as it
would eventually increase the linking number of the parental strands. Note that
gyrase would be burning ATP to pump (-) supercoils ahead of the fork
while topo IV would be burning more ATP to eliminate these very same (-)
supercoils once they diffuse through the fork and become left-handed
precatenanes. Moreover, the right-handed precatenanes present in (+)
supercoiled RIs would not be eliminated by topo IV. These observations call
into question the precatenane model. It is possible that in actively
replicating molecules, supercoiling does not diffuse through the replication
forks because they might not be able to rotate freely. The observation that
replication complexes are anchored to the bacterial membrane (Levine et al, 1998) suggests that there is a
topological barrier that would prevent diffusion of the (+) supercoiling
generated in the unreplicated portion as the fork advances to the replicated
part. In this case, precatenanes would not form. Experimental evidence for
precatenanes in vivo is not abundant and the few cases reported in the
literature are indirect. The occurrence of knotted replication bubbles
(Olavarrieta et al, 2002a,b,c; Sogo
et al, 1999; Viguera et al,
1996) was considered to be the best available evidence indicating
that precatenanes may form in (-) supercoiled, partially replicated
molecules in vivo (Postow et al,
1999). Further evidence supporting the occurrence of precatenanes
in vivo comes from experiments using small circular plasmids replicated
in Xenopus cell extracts. The significant increase in the number and
complexity of catenanes after partial inhibition of eukaryotic topo II (the
equivalent of prokaryotic topo IV) could only derive from pre-existing
precatenanes (Lucas et al, 2001). In most
of these cases, though, replication was impaired either by stalling the forks
or by inhibiting topo II. It is possible that precatenanes could form in
vivo only if progression of the replication forks is permanently stopped or
severely impaired. In other words, precatenanes might not form in vivo
during unimpaired DNA replication. They would readily form in vitro,
however, after DNA isolation and deproteinization, as then the forks would be
free to rotate. It is interesting to note that in E. coli cells, the
majority of topo IV activity is concentrated close to replication factories at
the cell centre and occurs mainly late in the cell cycle (Espeli et al, 2003; Sherratt,
2003). These findings could explain how topo IV is prevented from
eliminating left-handed precatenanes in (-) supercoiled RIs if such
precatenanes eventually form.
The topological changes that take place as a replicon replicates are
just beginning to be unravelled. Until this apparent topo IV decatenation
paradox is finally solved, it seems that during replication all the possible
topological forms RIs can adopt could have some role. The topological cycle of
a replicon appears to involve supercoiling, precatenation, knotting, catenation
and decatenation (see Fig 3). Whether or not the changes
that have been observed for small plasmids also apply to the large topological
domains of bacteria and linear eukaryotic chromosomes remains to be shown.
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Acknowledgements
Original research in the authors' laboratories was partially supported
by the Ministerio de Ciencia y Tecnología grants SAF 2001-1740 and BMC
2002-00546 (to J.B.S.) and by the Swiss National Science Foundation grants
3100-058841 and 3152-068151 (to A.S.).
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