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Biology of the Cell 00 (2003) 000-000
www.elsevier.com/locate/bicell
Scientiae Forum – Primer Review
Introduction to chromosome dynamics in mitosis
Erwan Watrin *, Vincent Legagneux
UMR 6061 CNRS, Université de Rennes I, Faculté de Médecine, 2 Avenue du Pr Léon Bernard, 35043Rennes cedex, France
Received 1 August 2003; accepted 27 August 2003
Abstract
To ensure that the genetic information, replicated in the S-phase of the cell cycle, is correctly distributed between daughter cells at mitosis,
chromatin duplication and chromosome segregation are highly regulated events. Since the early 1980’s, our knowledge of the mechanisms
governing these two events has greatly increased due to the use of genetic and biochemical approaches. We present here, first, an overview of
the replication process, highlighting molecular aspects involved in coupling replication with chromatin dynamics in mitosis. The second part
will present the current understanding of chromosome condensation and segregation during mitosis in higher eukaryotes. Finally, we will
underline the links that exist between replication and mitosis.
© 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.
Keywords: Cell division; Chromatin; Cohesin; Condensin; Topoisomerase II
1. Introduction
During the cell cycle, two critical steps involving chromatin are the duplication of the genome, occurring in S-phase,
and the segregation of the two sets of replicated chromosomes during anaphase. These two events are highly regulated in order to ensure that the genetic information is integrally and faithfully distributed into each daughter cell. In
mitosis, the chromatin is packaged into compact entities, the
mitotic chromosomes. This condensation process greatly reduces the volume of the replicated genomes to interphase
chromatin, contributes to the resolution of the replicated
sister chromatids and finally facilitates the subsequent separation of sister chromatids in anaphase.
In the past two decades, genetic and biochemical approaches have greatly contributed to the knowledge of the
molecular actors and the underlying mechanisms supporting
chromosome condensation and segregation. Although separated in time, these events are highly co-ordinated with each
other and with the replication process. A dysfunction in one
or more of these events may result in chromosome breakage
or aneuploidy, which could potentially contribute to the development of tumour.
The first part will present an overview of the replication
process, highlighting molecular aspects involved in coupling
* Corresponding author. Fax : 33 (0) 2 23 32 44 78.
E-mail address: [email protected] (E. Watrin).
© 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.
doi:10.1016/j.biolcel.2003.08.003
replication with chromatin dynamics in mitosis. The second
part will present the current understanding of chromosome
condensation and segregation during mitosis in higher eukaryotes. Finally, concluding remarks will underline the
links that exist between replication and mitosis.
2. DNA replication and sister chromatid cohesion
2.1. DNA replication
Once a cell begins to proliferate, the first crucial event is
the duplication of its genetic material.
In eukaryotes, this semi-conservative replication, catalysed by the holoenzyme point in the DNA polymerase, fires on
chromatin at numerous sites called origins of replication. In
budding yeast, origins of replication are short, consensus
sequences; on the contrary, replication can start at any DNA
sequence during early development of some metazoans (Xenopus laevis, Drosophila melanogaster). In mammalian
cells, the situation is somewhere between these two extremes. Eukaryote origins of replication direct the formation
of protein complexes that lead to the assembly of replicative
complex. Briefly, the six subunit origin recognition complex
(ORC) binds DNA sequences thus defined as origins of
replication. This complex binds DNA throughout the cell
cycle in yeast. In metazoans, however, it is still not clear
whether the ORC remains bound to chromosomes in mitosis.
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After mitosis, two additional proteins, Cdc6p and Cdt1p, and
a multisubunit complex, the MCM2-7 complex associate
with the ORC, together forming the pre-replication complex
(pre-RC). The pre-RC is matured into pre-initiation complex
(pre-IC) by the recruitment of additional factors, including
Cdc45 and Sld3. DNA polymerases are then recruited to
origins of replication, and synthesise new DNA strands. The
initiation of S-phase is triggered by different CDK-Cyclin
combinations depending on the species. CDKs are Cyclin
Dependent Kinases that regulate numerous cell events. The
first identified CDKs regulate progression through the cell
cycle. In addition to initiating replication, specific CDKs
inhibit re-initiation by preventing new pre-RC assembly, so
that replication occurs once and only once per cycle. Replication elongation depends on additional factors, among
which the DNA helicase PCNA (Proliferating Cell Natural
Antigen). During DNA synthesis, checkpoints ensure that
the replication machinery faithfully copies the genome (for
review on replication process, see Bell and Dutta, 2002 ; for
detailed description of the order of events during the chromosome replication cycle, see Diffley and Labib 2002). Replication is coupled to several other processes, such as sister
chromatid cohesion, post-replicative repair and imprinting
(epigenetic inheritance).
From one origin of replication emanate two replication
forks that progress in opposite directions along the DNA
fibre (bi-directional replication). Because of the double helical structure of DNA, progression of replication forks generates strains and supercoiling that must be dissipated by topoisomerase activities : actually, the region of DNA in front of a
running replication fork becomes overwound or positively
supercoiled. Some of the overwinding of the helix is transmitted to the region behind the replication fork causing the
intertwining of the two replicated regions of DNA fibres. The
main part of the resulting topological links are resolved
during replication by topoisomerases I and II (for details see
Lucas et al., 2001). Nonetheless, some links between newly
synthesised sister chromatids will persist until the metaphase
(see below).
2.2. Sister chromatid cohesion
Once DNA replication is achieved, each chromosome is
composed of two catenated sister chromatids that have to be
held together until they segregate, this can occur long after
duplication is completed. The maintenance of this tightlyheld-chromatid state, known as sister chromatid cohesion is a
prerequisite for the accurate distribution of the genetic information into the two daughter cells. Sister chromatid cohesion
is established during replication and provides a mechanism
by which paired sisters are recognised as such by the spindle
apparatus during mitosis : sister chromatids associate with
spindle microtubules via kinetochores. These are huge proteinaceous complexes that assemble on centromeres, which
are the main point where sister chromatids are held together.
Centromeres contain over 3 million DNA base pairs in humans, organised in blocks of tandemly repeated sequence. In
mitosis, sister kinetochores associate with microtubules emanating from opposite poles of the mitotic spindle, generating
poleward-pulling forces that tend to separate sister chromatids. Sister chromatid cohesion opposes these pulling forces
by maintaining the two sister chromatids together, thereby
generating tension that facilitates the correct biorientation of
sister chromatids on the mitotic spindle and subsequently,
their proper segregation. In addition to topological links
between sister chromatids, sister chromatid cohesion is ensured by a multisubunit complex called cohesin. Cohesin
contains a core complex of a heterodimer composed of two
SMC proteins (for Structural Maintenance of Chromosome),
namely Smc1 and Smc3. SMC family proteins are characterised by an amino-terminal nucleotide binding domain
(walker A motif), two central interacting coiled-coils separated by a hinge region and a carboxy-terminal domain
(walker B motif), that, when associated with the walker A
motif, constitutes an ATPase domain. Smc1 and Smc3 interact through their hinge regions. This dimer binds via its
globular ATPase domains a third protein, Scc1 that in turn
binds a fourth cohesin subunit, Scc3.
The cohesin complex associates with chromosomes from
telophase to the onset of the subsequent anaphase. The association of the cohesin complex with chromatin depends on a
distinct additional complex containing Scc2 and Scc4 proteins. Recent electron microscopy observations (Anderson et
al, 2002 ; Haering et al, 2002) together with biochemical
experiments (Haering et al, 2002 ; Gruber et al., 2003) have
provided new insights into cohesin structure leading to the
“ring model”, depicted in Figure 1. Each Smc protein constitutes one half of the cohesin ring by their homotypically
interacting coiled coil regions. Interacting by their hinge
regions, the two Smc proteins are also linked by the Scc1 that
interacts with Smc1 and Smc3 via its C-terminal and
N-terminal regions, respectively. The cohesin ring binds either unreplicated chromatids from telophase to S-phase or
duplicated chromatids from DNA replication to the onset of
anaphase, when proteolysis of Scc1 opens the ring, allowing
sister chromatids to segregate.
Before entry into mitosis, human cells possess in their
20 µm-diameter nucleus 46 chromosomes, each made of two
replicated sister chromatids, topologically linked and held
together by cohesin rings, that have to be separated and
equally distributed into each daughter cells. This separation
requires that chromatin is condensed into mitotic chromosomes and spatially organised relative to the mitotic spindle.
3. Mitotic chromosome condensation and segregation
3.1. Condensin complex, topoisomerase II and mitotic
chromosome formation
As mitosis begins, chromatin starts to condense into chromosomes. Biochemical experiments in Xenopus egg extracts
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Fig. 1. SMC protein structure and the ring model of cohesin.
A) SMC proteins are composed of an amino-terminal nucleotide binding
region (green) called the Walker A motif, two central interacting coiled-coils
(blue) separated by a flexible hinge region (orange), and finally, a carboxyterminal region, the Walker B motif (red). SMC proteins fold via the
interaction of their two coiled-coils. The association of the Walker A and B
motifs constitutes an ATPase domain. In the cohesin complex, Smc1 (dark
colours) and Smc3 (light colours) interact through their hinge region. B) The
ring model of cohesin structure : the heterodimer Smc1/Smc3 constitutes a
ring that encircles sister chromatids. This ring is closed by Scc1 (yellow) that
binds the ATPase domains of both Smc1 and Smc3, respectively, through its
C-terminal and N-terminal domains. In addition, Scc1 binds Scc3 (purple).
have provided major insights into the molecular actors of
chromosome condensation by identification and characterisation of a multisubunit complex associated with mitotic
chromosomes (Hirano and Mitchison, 1994). This complex,
named condensin, is composed of a heterodimer of SMC
proteins, but different from those in cohesin, namely
Smc2/XCAP-E (for Xenopus Chromosome Associated Pro-
3
tein) and Smc4/XCAP-C. This dimer, considered as the core
complex, interacts with three additional subunits, XCAP-D2,
XCAP-G and XCAP-H. Some condensin subunits have also
been characterised by genetic and biochemical approaches in
independent experiments (Saka et al., 1994 ; Strunnikov et
al., 1995 ; Cubizolles et al., 1998 ; Sutani et al., 1999). When
mitotic extracts are immunodepleted of condensin, exogenous chromatin fails to condense into mitotic chromosomes. The condensation is restored by adding back condensin, indicating that this complex plays an important role
in the condensation process. Condensin complex has also
been shown capable of introducing positive supercoils into
plasmids in the presence of topoisomerase I, in vitro. This
indicates that the condensin complex is able to maintain
constrained positive supercoils in plasmid DNA. This activity is thought to be involved in the mechanism of DNA
compaction, although the way this occurs still remains
speculative.
Condensation of chromatin into mitotic chromosomes is
not the mere compaction of a linear chromatin fibre, because
it has to deal with the topological links that remain between
sister chromatids once replication is complete. The decatenation of sister chromatids is ensured by the topoisomerase II
activity, which as a consequence is required for resolution
and segregation of replicated genome in anaphase. As topoisomerase II does not discriminate between catenation and
decatenation, its activity must be directed towards sister
chromatid resolution. Interestingly, topoisomerase II has
been shown to interact with Barren, the Drosophila melanogaster homologue of the XCAP-H condensin subunit, providing a physical link between compaction and resolution
(Bhat et al., 1996). This could explain the phenotypes of
condensin subunit disruption. Indeed, they mainly show
resolution defects in vivo, rather than dramatic condensation
defects, at least in higher eukaryotes. Indeed, even if results
from different organisms indicate a clear role of condensin in
chromosome condensation, it is also clear that condensin
cannot account for the entire chromatin compaction process.
Rather, condensin appears to be a key player in the resolution
of sister chromatids, possibly by regulating topoisomerase II
activity. However, recent experiments in cycling extracts
report that topoisomerase II activity is required prior to
mitosis and independently of condensin for chromatin to
condense properly during mitosis (Cuvier and Hirano, 2003).
In addition to these catalytic roles of compaction and
resolution, the condensin complex and topoisomerase II also
play a structural role in maintaining the mitotic chromosome
architecture. In mitosis, condensin and topoisomerase II display a similar chromosomal localisation, staining the axis of
sister chromatids (see Figure 2, A). Topoisomerase II is
present on chromosomes throughout the cell cycle, whereas
immunofluorescence experiments indicate that the condensin complex is loaded onto chromosomes during late
prophase, a stage where chromosome condensation is already largely completed (Figure 2, b). This indicates that
condensin is not the only chromatin condensing complex.
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Fig. 2. Dynamic localisation of topoisomerase II and condensin during mitosis. Pictures show HeLa cells fixed in methanol and stained with antibodies against
topoisomerase II and hCAP-D2.
A) Topoisomerase II (red) and condensin localise on the chromosomal axis in metaphase as revealed by immunofluorescence. B) Topoisomerase associates with
chromosomes during mitosis, whereas condensin binds to chromosomes from the end of prophase to late anaphase.
The chromosomal localisation of condensin is not yet elucidated, but it has been shown that XCAP-D2 is stoichiometricaly required to localise XCAP-H, but not XCAP-E (Watrin
et al., 2003) in Xenopus egg extract. Moreover, AKAP-95, a
nuclear-matrix protein, is required to address condensin onto
chromosomes in mitotic human cell extract, via a direct
interaction with hCAP-H, the human homologue of
XCAP-H. Interestingly, an interaction has also been described between XCAP-H and hCAP-D2 (the human homologue of XCAP-D2) in a two-hybrid assay (Eide et al., 2002).
These results suggest that both CAP-D2 and AKAP-95 are
involved in chromosomal localisation of condensin via their
interaction with CAP-H. Finally, the chromosomal localisation of condensin depends on the presence of aurora B kinase
in both Drosophila melanogaster (Giet et al., 1998) and
Caenorhabditis elegans (Kaitna et al., 2002)(see below).
Dissociation of condensin complexes from chromatin occurs
at the end of anaphase, by an unknown mechanism, at about
a time when cohesin complexes are loaded onto chromatin
(for comprehensive review on condensin and chromosome
condensation, see Swedlow and Hirano, 2003).
3.2. Passenger proteins and chromosome bi-orientation
Passenger proteins are characterised by their behaviour
during mitosis : localised onto chromosomes upon entry into
mitosis, passenger proteins are enriched in centromeric regions from the end of prophase to metaphase. At the onset of
anaphase, they relocalise to the central region of the micro-
tubule spindle (see Figure 3). Up to now, four proteins share
this particular behaviour : the mitotic kinase aurora B, the
inner centromere protein INCENP, the IAP-related (inhibitor
of apoptosis) protein survivin and finally, a fourth newly
described passenger protein, CSC-1. These proteins seem to
be mainly involved in coordinating the behaviour of chromosomes, mitotic spindle and cleavage furrow during mitosis.
In particular, the first three proteins are involved in phosphorylation of histone H3, bipolar attachment of spindle microtubules to kinetochores, chromosome condensation and segregation.
Aurora B is involved in both chromosomal localisation of
condensin and histone H3 phosphorylation, two concomitant
events that occur during prophase (Giet and Glover, 2001 ;
Kaitna et al., 2002 ; Losada et al., 2002 ; MacCallum et al.,
2002). However, although an attractive hypothesis is that this
chromatin modification triggers condensin recruitment, there
is no evidence for a causal link between these two events.
To allow sister chromatid segregation at anaphase, spindle
microtubules have to bind sister chromatid kinetochores.
Among the different ways microtubules can attach to kinetochores (merotelic, syntelic and amphitelic attachment see
Figure 4), only amphitelic attachment will allow migration of
sister chromatids to opposite poles. Microtubules act as
“blind kinetochore-catchers”. Control mechanisms ensure
the correct (amphitelic) attachment of microtubules to kinetochores. One of the major role of aurora B-INCENPsurvivin complex is to favour the correct bipolar attachment
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Fig. 3. Dynamic behaviour of passenger proteins in mitosis.
The pictures show HeLa cells fixed in methanol and stained with antibodies against Aurora B. When mitosis starts, Aurora B localises on chromosomes, mainly
at centromeres. At the onset of anaphase, Aurora B dissociates from chromosomes and relocalises to the middle part of the mitotic spindle, and finally binds to
the midbody in telophase.
of spindle microtubules to kinetochores by destabilising incorrect attachments rather than directly inducing amphitelic
attachment (see Figure 4 ; for review see Tanaka, 2002). It
must be noted that misattached or unattached chromosomes
trigger the activation of the mitotic spindle checkpoint that
prevent premature separation of sister chromatids. This
checkpoint involves regulatory proteins that bind Cdc20, the
activator of the anaphase-promoting complex or cyclosome
ubiquitin ligase (APC/c). This blocks ubiquitination and
thereby degradation of both securin and cyclin B (see below ;
for review concerning mitotic spindle checkpoint, see
Musacchio and Hardwick, 2002).
Fig. 4. Aurora B favours correct attachments of microtubules to kinetochores by destabilising incorrect ones.
During prometaphase and metaphase, microtubules emanating from opposite poles of the mitotic spindle bind kinetochores in a random manner. As
only amphitelic attachments are suitable for correctly executed anaphase,
incorrect attachments are converted via the Aurora B signalling pathway to
monotelic attachments, until they develop amphitelic ones. Until every
attachment is correctly aligned, the spindle checkpoint is activated, preventing anaphase and precocious chromosome separation.
3.3. Cohesin release and chromosome segregation
To allow sister chromatids to separate at the onset of
anaphase, topological links that persist after replication are
resolved by topoisomerase II activity (see above). In addition, cohesin that encircles replicated sister chromatids after
replication has to be removed from chromosomes. In vertebrates, two distinct pathways trigger cohesin release during
mitosis (Waizenegger et al., 2000 ; Sumara et al., 2002).
During prophase, the bulk of cohesin present on chromosome arms is removed by its phosphorylation by Polo-like
kinase, probably reducing the affinity of cohesin for chromatin. A small amount of cohesin (about 5%) remains on chromosomes after prophase, mainly on pericentromeric regions.
It is not known if the remaining pool of cohesin is insensitive
to Polo-like kinase phosphorylation due to differences in
composition or to localisation in regions inaccessible to
Polo-kinase. This remaining pool of centromeric cohesin
participates to the bi-orientation of chromosomes on the
mitotic spindle by holding sister chromatids together.
Once all chromosomes are correctly bi-attached to spindle
microtubules, the spindle checkpoint is inactivated, thereby
allowing anaphase to proceed. The onset of anaphase is
determined by the degradation of cyclin B by the 26 S
proteasome (for review see Peters, 2002), via its ubiquitination by the APC/c ubiquitin ligase. Dissociation of the remaining cohesin is triggered by the cleavage of cohesin’s
Scc1 subunit by separase, a cysteine protease. Separase is
kept inactive till anaphase by binding to securin, an inhibitory chaperone that is degraded by the APC pathway at the
onset of anaphase. Once all cohesin has been removed,
poleward-pulling forces exerted by spindle microtubule allow the two sets of chromosomes to move to opposite poles
of the cell (for outstanding reviews on segregation see
Nasmyth, 2002 and Petronczki et al., 2003).
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4. Concluding remarks
References
Chromosome condensation and segregation are fundamental events that have to proceed correctly in order to
ensure that the two sets of replicated chromosomes are faithfully transmitted to each daughter cells.
As mitotic chromosome condensation is linked to DNA
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Acknowledgements
The author’s research is supported by grants from the
Association pour la Recherche contre le Cancer, Contract
Number 5711. CNRS UMR 6061 is a component of the
Federative Research Institute IFR97, Génomique Fonctionnelle et Santé. E.W. is recipient of a fellowship from the
French Ministère de la Recherche et des Nouvelles Technologies.
We are very grateful to Carole Gautier-Courteille and
Régis Giet for comments on the manuscript.
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