The Dynamic Cell
Dividing the goods: co-ordination of chromosome
biorientation and mitotic checkpoint signalling by
mitotic kinases
Geert J.P.L. Kops1
Department of Physiological Chemistry and Cancer Genomics Centre, UMC Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Abstract
Error-free chromosome segregation during cell division relies on chromosome biorientation and mitotic
checkpoint activity. A group of unrelated kinases controls various aspects of both processes. The present short
review outlines our current understanding of the roles of these kinases in maintaining chromosomal stability.
Chromosome biorientation: a tale of two
sisters
Faithful segregation of chromosomes to resulting daughter
cells in mitosis relies on chromosome biorientation and
mitotic checkpoint signalling (Figure 1). In early mitosis,
the two copies of a duplicated chromosome (i.e. sister
chromatids) need to attach via their kinetochores to spindle
microtubules emanating from opposite sides of the cell in a
process known as biorientation (reviewed in [1]). Crucial for
this is efficient microtubule capture by the kinetochores of
each sister chromatid (reviewed in [2]). Quite a few duplicated
chromosomes, however, initially attach with each sister to
microtubules from a single pole rather than opposite poles (a
‘syntelic’ attachment). This error in attachment needs to be
corrected for biorientation to occur (reviewed in [3]). Once a
duplicated chromosome has bioriented, forces intrinsic to the
mitotic spindle move that chromosome to the spindle equator
in a process termed chromosome ‘alignment’ or ‘congression’.
Biorientation is, however, not an absolute requirement for
congression, as non-bioriented chromosomes can congress by
using microtubules from bioriented chromosomes as tracks to
guide them to the cell equator [4]. On biorientation of the final
chromosome, removal of cohesion between the sister chromatids coupled with pulling forces from the opposing spindle
poles and possibly molecular motors at the kinetochores
ensures that each sister is dragged to opposite sides of the cell.
The mitotic checkpoint
The irreversible event of chromosome segregation needs to
be prevented until each and every duplicated chromosome
is bioriented. Premature onset of chromosome segregation
causes unequal chromosome distributions, or aneuploidy,
Key words: aneuploidy, chromosome, kinase, kinetochore, mitotic checkpoint, segregation,
spindle.
Abbreviations used: APC/C, anaphase-promoting complex/cyclosome; Bi-MC, biorientation and
mitotic checkpoint, Cdc20, cell division cycle 20; CENP-E, centromere protein E; CIN, chromosomal
instability; MCC, mitotic checkpoint complex; MVA, mosaic variegated aneuploidy; PRP4, premRNA processing factor 4.
1
email [email protected]
Biochem. Soc. Trans. (2009) 37, 971–975; doi:10.1042/BST0370971
which is a leading cause of birth defects and the most common
genetic alteration among solid tumours. This inspired the
hypothesis that aneuploidy could be a contributing
factor in carcinogenesis (reviewed in [5]). Attachment of
chromosomes to spindle microtubules, a prerequisite for
biorientation, is monitored by a cell-cycle checkpoint known
as the spindle assembly checkpoint or the mitotic checkpoint,
which halts chromosome segregation and subsequent exit
from mitosis when as little as one single chromosome has
not established attachments (Figure 1) [6,7].
Unattached kinetochores act as scaffolds to recruit and activate components of the checkpoint machinery, culminating
in inhibition of the E3-ubiquitin ligase APC/C (anaphasepromoting complex/cyclosome) that controls chromosome
segregation and exit from mitosis (reviewed in [8]). Together
with its co-activators Cdc20 (cell division cycle 20) and
Cdh1, the APC/C promotes anaphase onset and progression
through the cell cycle by ensuring the ubiquitin-dependent
destruction of securin and cyclin B (reviewed in [9]). The
mitotic checkpoint inhibits Cdc20-dependent activation of
the APC/C until all kinetochores are properly attached.
This ensures an extension of mitosis to allow sufficient
time to achieve kinetochore–microtubule attachments and
biorientation. The first identification of components of the
mitotic checkpoint stems from studies in the baker’s yeast
Saccharomyces cerevisiae that screened for mutants that could
not survive growth in the presence of a spindle poison [10–
12]. Orthologues of these mutants, Bub1, Bub3, Mad1, Mad2,
Mad3 and Mps1, were later identified to be crucial for mitotic
checkpoint activity in a host of model systems, including
human tissue culture cells (reviewed in [13–16]). Many
additional components have been suggested to participate in
checkpoint signalling in human cells (reviewed in [16]).
Essential for the assembly of an APC/C inhibitor by
unattached kinetochores is the activation of Mad2 by dimerization with a Mad1–Mad2 heterodimer that is stably bound
to unattached kinetochores. This dimerization converts an
inactive Mad2 molecule into an active one that can participate
in Cdc20 binding and APC/C inhibition (reviewed in [17]).
Two of the current models for checkpoint function are
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Figure 1 Two processes essential for error-free chromosome
segregation
In early mitosis (prometaphase), the mitotic checkpoint prevents
cell-cycle progression while chromosomes attempt to attach with each
copy to opposite poles (biorientation). Once productive attachment
of every chromosome is reached and chromosomes have bioriented
(metaphase), the checkpoint is satisfied and chromosome segregation
is allowed.
Figure 2 Two models of mitotic checkpoint-mediated inhibition
of the APC/C
See the text for details.
depicted in Figure 2. In the relay model, activated Mad2
binds Cdc20 and transfers it to BubR1–Bub3 dimer (BubR1
has sequence similarity to yeast Mad3). BubR1–Bub3–Cdc20
complexes can bind the APC/C, where BubR1 functions as a
pseudo-substrate inhibitor of the APC/C via its N-terminal
destruction [KEN (Lys-Glu-Asn)] motifs [18–22]. In the
MCC (mitotic checkpoint complex) model, activated Mad2
and the Bub3–BubR1 dimer bind Cdc20 and form a tetrameric complex. This tetramer, coined the MCC, then inhibits
the APC/C as described above [23–25]. One clear difference
between these models is that each predicts different amounts
of Mad2 to be present in APC/C complexes, but there is currently no consensus on this seemingly straightforward issue.
In line with the relay model, some studies have found little
Mad2 complexed to BubR1–APC/C in checkpoint-activated
cells or have found no need for Mad2 in the direct inhibition of
the APC/C by BubR1 [20,22,26]. On the other hand, purifications of inhibited APC/C complexes from mitotic cells
contain clearly detectable Mad2, even to near-stoichiometric
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Authors Journal compilation levels with BubR1 and APC/C subunits [25,27]. Many other
issues will need to be addressed before a clear molecular
description of the mitotic checkpoint can be formulated. For
instance, does BubR1 need to be activated by unattached
kinetochores to be able to bind Mad2-bound Cdc20 or inhibit
the APC/C? Is dimerization of Mad2 regulated by other
factors, such as phosphorylation or protein components? Is
there a direct role for Mad2 in APC/C inhibition? How does
pseudosubstrate inhibition of the APC/C by BubR1 take
effect molecularly? What is the role of the many other proteins identified as important for mitotic checkpoint activity?
In vitro insights into how Cdc20 activates APC/C activity
towards mitotic substrates might provide clues as to how the
inhibitory complex prevents this, and what the roles are of
the various components proposed to constitute the inhibitor.
Inhibition of the APC/C is relieved shortly after the
final kinetochore has engaged in productive attachments
with spindle microtubules. Several mechanisms to shut down
production of the inhibitor by unattached kinetochores or to
disassemble inhibitory complexes that were produced prior to
final attachment have been proposed and are reviewed in [16].
For example, p31comet is a structural mimetic of Mad2 and can
thus prevent Mad2 dimerization and may additionally aid disassembly or inhibition of proposed MCC complexes [28–30].
On attachment of the final kinetochore, several or all of these
mechanisms combine to rapidly allow activity of APC/C
towards cyclin B and securin and promote mitotic progression beyond anaphase. It is not unlikely that unattached
kinetochores, besides promoting formation of the inhibitor,
also actively prevent disassembly of the inhibitor. Such a
tight control of the amount of inhibitor could translate the
attachment state of a kinetochore to a switch-like behaviour
of the mitotic checkpoint, ensuring rapid activation of the
APC/C and commitment to anaphase upon attachment of
the final kinetochore. The coming years will probably witness
a wealth of insight into the mechanisms of inhibition of the
mitotic checkpoint signal and how that is regulated in space
and time.
Kinase signalling in checkpoint control and
chromosome alignment
The processes of biorientation and checkpoint signalling are
highly dynamic. Kinetochore–spindle microtubule connections need to be established and severed rapidly to allow
biorientation and alignment. In addition, the checkpoint
needs to be switched on as soon as misattachments threaten
faithful chromosome segregation and needs to be inactivated
equally rapidly once biorientation has been achieved. Not
surprisingly therefore, kinases play important roles in these
processes. Moreover, as the kinetochore of a single unattached
chromatid is sufficient to inhibit all cellular APC/C activity,
the signal from each kinetochore needs to be amplified
significantly, a process that may be facilitated by kinases.
So far, the kinases Mps1, Bub1, BubR1, NEK2A (never in
mitosis A-related kinase 2A), PRP4 (pre-mRNA processing
factor 4) and TAO1 (thousand-and-one amino acid protein
The Dynamic Cell
1) have been directly implicated in checkpoint signalling
in human cells and most are also crucial for chromosome
biorientation (unreported for PRP4) [31–42]. For practical
purposes, this group of enzymes will be referred to here as the
subfamily of Bi-MC (biorientation and mitotic checkpoint)
kinases. Interestingly, in the three instances in which more
details on the role of the Bi-MC kinases were reported, each
of them was found to impact biorientation in different ways.
In all cases, however, this function is independent of their
roles in the mitotic checkpoint, as inactivating the mitotic
checkpoint by virtue of Mad2 depletion has no consequence
for biorientation [37]. The establishment of stable interactions
between kinetochores and spindle microtubules requires
BubR1 [32,37]. Cells depleted of BubR1 have unattached
kinetochores, and stable attachments can be reinstated
when Aurora B kinase activity is additionally inhibited.
As Aurora B can destabilize kinetochore–microtubules
interactions (reviewed in [3]), this suggests that BubR1
somehow keeps Aurora B activity in check, thus allowing
kinetochore–spindle interactions to form. BubR1 further
interacts with CENP-E (centromere protein E), a plusend-directed microtubule motor [31,43]. CENP-E may
participate in BubR1’s control over Aurora B since depletion
of CENP-E in Drosophila S2 cells was reported to restore
stable attachments after BubR1 depletion [44]. It is not known
whether BubR1 kinase activity is required for the stabilization
of chromosome attachments. Studies in frog extracts, human
cells and mouse cells are contradictory with respect to this
question [21,45–48]. Careful gene-replacement studies or the
identification of a critical substrate will be able to settle this
issue. Another aspect of biorientation is regulated by the Bub1
kinase, which ensures conversion of a lateral attachment into
an end-on one [36,39]. It is unknown how this conversion
takes place, and the role of Bub1 in this is therefore also poorly
described. In addition, Bub1 maintains sister chromatid
cohesion by ensuring the centromere localization of the
cohesin protector shugoshin [49,50]. As shugoshin-depleted
cells also have unstable kinetochore–microtubule interactions
[51], it is possible that this function of Bub1 is related to
its role in the lateral-to-end-on conversion of kinetochore–
microtubule attachments. Although Bub1 kinase activity is
needed for checkpoint control, at least in fission yeast and
frog extracts [52,53], it has not yet been reported whether it is
needed for biorientation as well. Finally, we and others have
recently shown that Mps1 is dispensable for stable attachments or lateral-to-end-on conversion but instead controls
attachment-error correction. In yeast and human cells, Mps1
kinase activity ensures biorientation by facilitating the correction of syntelic and possibly merotelic attachments [35,54].
Although not apparent in yeast cells, Mps1 was shown to
promote Aurora B activity via direct phosphorylation of its
auxiliary protein Borealin in human cells [35].
Bi-MC kinases in pathologies
All human aneuploidies during development result in
embryonic lethality, except certain combinations of sex chro-
mosomes and trisomies 13, 18 and 21, which lead to severe
birth defects [55]. In addition, comprehensive analysis of over
20 000 tumour samples revealed that aneuploidy is the characteristic most commonly shared by all tumours [56]. Various
cancer cell lines show CIN (chromosomal instability),
meaning they frequently lose and gain whole chromosomes
during divisions. A number of observations have lent support
to the hypothesis that aneuploidy, despite providing cells
with significant proliferative disadvantages in vitro [57,58],
can contribute to or even drive carcinogenesis. Mice in which
aneuploidy is induced have a significant increase in sensitivity
to carcinogens and can co-operate in a synergistic fashion
with tumour suppressor mutations for the outgrowth of
tumours (reviewed in [59]). Normal diploid cells can become
aneuploid when any of various mechanisms that all centre
around ensuring fidelity of chromosome segregation during
mitosis are compromised. It has thus been proposed that
mitotic checkpoint activity may be weakened in tumour cells,
allowing for occasional chromosome mis-segregation events.
Although various studies using suboptimal assays (reviewed
in [5]) have claimed weakened or absent mitotic checkpoints
in tumour cell lines or tumour samples, recent careful analyses
of a total of five CIN cancer cell lines showed that chromosome mis-segregations in vitro are not caused by potential
defects in the mitotic checkpoint in these cell lines [60,61].
Correlations between expression/mutations in the Bi-MC
kinases and aneuploidy-related pathologies have been
reported, but causal links have not been established. For
instance, Mps1 mRNA expression in a panel of 12 breast
cancer cell lines and 9 primary tumour samples was found to
be increased up to 500 times relative to normal cells [62]. This
may influence stability of kinetochore–spindle interactions
and thereby increase the frequency of chromosome missegregations. Of course, such overexpression of a kinase
may alternatively influence processes that are unrelated to
its endogenous functions and thereby contribute to the
transformed phenotype. In an example of a very strong
correlation between alterations of a Bi-MC kinase and a
disease, germline mutations in the BUB1B gene encoding
BubR1 were recently reported in a recessive condition called
MVA (mosaic variegated aneuploidy), a characteristic of
which is the development of childhood cancer [63,64]. In a
British cohort of MVA patients, biallelic mutations in BUB1B
were found that combined a predicted protein truncation
(removing the C-terminal kinase domain) with a missense
mutation, often located in or near the kinase domain [63]. In a
Japanese cohort, monoallelic mutations were found, mostly,
but not exclusively, predicted to result in a truncated protein
from which the kinase domain is removed [64]. In these
patients, expression from the second, non-mutated allele was
reduced and this correlated significantly with a certain haplotype. Although not assayed entirely correctly, fibroblasts
from a Japanese MVA patient appeared to have a weakened
mitotic checkpoint response to spindle microtubules and
displayed elevated amounts of micronuclei, an indication of
chromosomes missegregations. A thorough analysis of the
effect of the MVA mutations on BubR1 function and
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Figure 3 Bi-MC kinases integrate distinct processes required for
proper chromosome segregation
Bi-MC kinases promote biorientation and prevent premature chromosome segregation by activating the mitotic checkpoint. A molecular
description of their role in these processes (question marks) will provide
valuable insight into how cells ensure correct chromosome segregation.
the fidelity of chromosome segregation is needed to find
out how aneuploidy could arise in the MVA patients. Such
insights may also prove valuable for our understanding of
aneuploidies in sporadic diseases such as cancer.
Concluding remarks
A general principle is emerging in which kinases that set up the
requirements for faithful chromosome segregation also signal
to the cell-cycle machinery to halt until those requirements
are met. These kinases are therefore crucial in the maintenance
of chromosomal stability, and molecular insights into their
activities will shed light on how chromosome segregation is
regulated at the molecular level (Figure 3).
Funding
Work in the laboratory of G.J.P.L.K. is supported by the Cancer
Genomics Centre, the Netherlands Proteomics Centre, the
Netherlands Organisation for Scientific Research and the Dutch
Cancer Society.
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Received 15 April 2009
doi:10.1042/BST0370971
C The
C 2009 Biochemical Society
Authors Journal compilation 975