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The cell cycle

Article  in  Philosophical Transactions of The Royal Society B Biological Sciences · December 2011

DOI: 10.1098/rstb.2011.0274 · Source: PubMed

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 Phil. Trans. R. Soc. B (2011) 366, 3494–3497
doi:10.1098/rstb.2011.0274

Introduction

The cell cycle

‘Dividing cells pass through a regular sequence of cell Werven & Amon [7] present an accessible and wide-
growth and division, known as the cell cycle’, accord- ranging survey of the process in budding yeast, fission
ing to a college textbook of biology published in 1983 yeast and higher eukaryotes that makes clear what a
[1], 5 years before the underlying principles of control delicately regulated process it is. Certain features
were first laid bare during 1988, the annus mirabilis of seem to be common: the existence of a ‘master regula-
cell cycle research [2,3]. One of the key architects of tor’ whose activity depends critically on a very
that revolution, Paul Nurse, was elected as President particular combination of nutritional or developmental
of the Royal Society in 2010, and this volume is signals, as well as downstream regulatory protein
intended in part as a tribute and in part as a reflection kinase cascades, in particular the TOR pathway and
of what we now know, and what remains still to be the cyclic AMP-dependent protein kinase. For some
found out about cell proliferation. Lest we forget that reason, functioning mitochondria are apparently also
cells have fates other than their own reproduction, required for successful gamete formation in yeast and
Pat O’Farrell [4] reminds us that many cells in our mice. Presumably, that has only been true since
bodies survive for long periods in a quiescent state. oxygen entered Earth’s atmosphere two and a half
He considers quiescence from the perspective of the billion years ago.
developmental biologist, and sees growth factors as In ‘normal’ cell cycles, there is a gap between the
surrogates for nutritional signals. He surveys the com- end of mitosis and the start of DNA replication, and
plexity and the richness of growth control in higher control of the G1 to S transition is an important
eukaryotes, rightly pointing out what an important point of no return in the cell cycle. Cross et al. [8] dis-
topic for future research this remains. This problem cuss the evolution of control networks at this stage of
is also attacked from the perspective of the single the cell cycle, comparing yeast with plants and ani-
starving cell by Yanagidai, who have been recently mals. They find that many individual regulators have
studying the effects of nitrogen or glucose deprivation either undergone huge sequence divergence from the
on fission yeast [5]. It turns out that the results are last common ancestor or have evolved from different
daunting. Wild-type yeast undergoes two rapid divi- origins. Despite this, the topology and dynamic prop-
sions to generate quasi-spherical cells if they are erties of networks have striking similarities. Diffley [9]
suddenly deprived of nitrogen, and undergoes startling looks at the control of initiation of DNA replication
changes in intracellular morphology and metabolism and again notes the variety as well as the redundancy
that remain difficult to comprehend. Interestingly, of mechanisms that ensure the genome is replicated
defects in these adaptions are accompanied by cell once and only once each time a cell divides. Arguing
death and hundreds of different genes, in many distant from simple assumptions, he points out that suppres-
pathways, are required to respond to starvation or to sion of re-replication must be close to 100 per cent
‘wake up’ when better times come along. efficiency and that a combination of mechanisms,
Long-term survival, we must remind ourselves, each with a small but finite failure rate, is necessary
requires not only cell division but also sex. Dan to reduce the overall failure rate to acceptable levels.
Mazia, who was the guru of cell division of the High fidelity is also a major consideration for the
1950s and 1960s, put it thus: ‘More often than not, control of key cell cycle transitions. The penalty for
questions beginning with ‘Why’ are inane and of no failure is high, the difference between success and fail-
service in scientific discourse. In biology, they some- ure is tiny, and mechanisms for assuring accuracy are
times make sense. If we ask why cells must divide, numerous and robust. Having evolved over billions of
the answer can be given in terms of what happens if years they may also be rather complicated and difficult
they do not. The answer is that they die, no matter to understand, as is the case with the so-called S-phase
what criterion of death we apply’ [6, pp. 82– 83]. checkpoints, discussed in detail by Labib & De Piccoli
This applies to organisms as well as cells, of course, [10]. As soon as people realized the importance of
and it is still somewhat mysterious that we humans DNA and DNA replication for cells, in the early
can all trace our ancestry back several billion years, 1950s, they tested the effects of ionizing radiation
yet we are all mortal. The continuity of the germ and discovered that normal cells quickly stopped
cells is something that successfully evolved, but is synthesizing DNA after X-ray damage (apart from
hard to explain and rarely examined. Yet, formation very rare mutant individuals, who were extremely sen-
of gametes is amenable to genetic analysis, and van sitive to X-irradiation and turned out—many years
later—to carry mutations in the ATM protein
kinase). These irradiated cells did not enter mitosis.
One contribution of 16 to a Theme Issue ‘The cell cycle’. After intense study, largely by geneticists, because
3494 This journal is q 2011 The Royal Society
 Introduction. The cell cycle T. Hunt et al. 3495

biochemical analysis for such complex systems is for Uhlmann et al. [13] take some trouble to examine
the most part too difficult, we are now aware of whether ‘checkpoints’ impose order on the cell cycle,
many if not most components of the S-phase check- and conclude that, on the whole, they do not. We
point, but it is still difficult to appreciate how the note, however, that the concept of checkpoint, while
system really works. Replication forks and collapsed highly popular and therefore much abused in the
replication forks are complicated structures and the literature, is often inappropriate in the context of the
details of how damage is sensed, signalled and repaired cell cycle as well as being rather fuzzy on close inspec-
are complicated and only gradually being worked out tion. In an earlier generation, before yeast genetics was
in mechanistic detail. The virtue of Labib’s account applied to cell cycle control, people like Dan Mazia
lies in its historical approach and his attention to used to talk about ‘Points of no return’ rather than
describing the experiments that underlie our present ‘Checkpoints’. The idea of the checkpoint is that you
understanding. Langerak & Russell [11] also discuss may not proceed to the next process or event until
the effects of DNA damage on cell cycle progression the one in which you are presently engaged is com-
and vice versa, concentrating on the mechanisms that plete: a quality control check. But there is something
repair double-strand breaks in DNA. These are largely else as well—once you have finished a task and been
twofold, non-homologous end joining (NHEJ), which allowed to pass on, you cannot go back. This applies
tends to occur when DNA is broken during the G1 equally to the G1 – S, the G2 – M and the metaphase
phase of the cell cycle, and homologous recombination to anaphase transitions. Uhlmann et al. [13] argue
(HR), a largely error-free repair process that uses that even if the level of Cdks activity has an important
sister chromatids to reconstruct lost DNA sequences. role in determining entry into S or M, regulation of
The latter requires production of long stretches of phosphatase activity plays an equally important part.
single-stranded DNA that search for neighbouring The various thresholds for cell cycle transitions are set
homologous DNA sequences and subsequently invade by ratios of kinase activity to phosphatase activity and
them. The abundance and the activity of a large cast not by kinase activity per se. This theme continues in
of cofactors are regulated in such a way as to promote the contribution from Domingo-Sasanes et al. [14],
NHEJ during G1, when sister DNAs are absent, and who restrict their discussion to the control of mitosis,
HR during S and G2, when they are present. but focus on the recently discovered role of greatwall
A key issue in cell cycle studies has been the nature of kinase as a controller of protein phosphatases that both
the triggers for the onset of DNA replication and mito- regulate and antagonize Cdks at the G2–M transition.
sis. Much to everyone’s surprise, both turn out to This brings us to the end of the cell cycle, or the
be triggered by similar molecules, namely S- and beginning of the next, the metaphase to anaphase
M-phase-specific cyclin-dependent kinases (CDKs), transition. Musacchio [15] entitles his piece ‘Spindle
and almost every article in this issue refers to these key assembly checkpoint: the third decade’, inviting the
cell cycle regulators. An important question about query, what’s taking you so long? The answer is that
these enzymes, apart from their regulation, is their sub- this is a very complicated piece of machinery involving
strate specificity. In particular, and this was confusing in both hardware (the kinetochore itself, and its connec-
the early days of the modern era of cell cycle studies, tion with spindle microtubules) and software—the
how can it be that the same kinase initiates both S and error correction mechanisms and surveillance mechan-
M phase? Why, for example, do cells undergo DNA isms that constitute the spindle assembly checkpoint
replication and not attempt to enter mitosis at the first (SAC). Interestingly, this regulatory system, unlike
appearance of CDK activity? Moreover, why do not other the so-called checkpoints, has little or no role
cells re-replicate their chromosomes when a second in repairing the damage sensed and appears solely con-
rise in CDK activity triggers mitosis? Two explanations cerned with regulating cell cycle progression. At least
seemed possible at first: one was that different cyclins three or four protein kinases (and presumably their
imbued Cdks with different properties, so S-phase counterpart phosphatases) are involved as well as
cyclins promote S phase and M-phase cyclins catalyse specific regulatory proteins such as Mad2. Working
mitosis. But an alternative, originally suggested by out how the SAC functions will require greater under-
Paul Nurse and co-workers [12], is that it takes only a standing of kintetochore structure as well as further
little Cdk activity to initiate S phase, but more to enter structural work on its target, the anaphase-promoting
M phase. The available evidence suggests that the complex/cyclsome (APC/C). Nevertheless, it is clear
level of activity is indeed part of the story, as Uhlmann that the structural approach has already been extre-
et al. [13] discuss in their article. However, this is only mely illuminating. At the moment, it looks as if the
part of the story. Whether a cell enters to undergo mechanical basis for the tension sensor may be noth-
DNA replication or mitosis in response to a rise in ing more complicated than a substrate being pulled
Cdk activity is as much determined by the presence or beyond the reach of a tethered kinase. We may hope
absence of substrates or structures for these kinases to that some of the other seemingly complex features of
work on. Thus, the reason why Cdks do not trigger S the mitotic checkpoint will proved to have a similarly
during G2 is that the pre-replication complexes required simple basis, once we understand them.
to initiate DNA replication are absent from this stage of David Barford’s [16] magisterial review of the APC/
the cell cycle. Likewise, G1 cells that have not yet repli- C depends even more so on structural determination,
cated their DNA do not possess a pair of sister but his recent impressive advances required him to
chromatids nor even the cohesion that will hold these work out ways of making large quantities of this enor-
together, and cannot undergo anything resembling a mous, complicated multi-subunit complex. As he
physiological mitosis until these have been produced. describes, we can begin to see how the thing works,
Phil. Trans. R. Soc. B (2011)
3496 T. Hunt et al. Introduction. The cell cycle

metakinesis and
division preparations anaphase division
metaphase
‘disappearance’
of nucleoli reappearance of
nucleoli
chromosome reproduction
chromosomal
RNA
reappearance of
chromosome ‘condensation’
nuclear membrane
breakdown of separation of
nuclear membrane sister chromosomes swelling or uncoiling
metakinesis
of chromosomes
alignment of
chromosomes chromosome movement
towards poles
kinetochores
connected
trigger? to poles spindle elongation
breakdown of
spindle
enlargement of asters spindles and asters
formation

synthesis of substances cytokinesis

interzonal
of achromtaic figure RNA

duplication + splitting
of centrioles
poleward separation
of centrioles energy reservoir

development of asters

energy
reservoir

time

Figure 1. Mazia’s diagram of mitosis with the starting pistol (‘Trigger?’). Adapted from Mazia [6].

although mysteries still remain, particularly in its con- necessary to begin to make sense of biological
trol. This is connected with the previous paper, of models. He also provides a useful definition for sys-
course, because somehow the SAC can reliably amplify tems biology: ‘It is the approach of collecting
a signal from a single kinetochore to inhibit millions of quantitative biological information at one level of com-
APC/Cs, and somehow (as anyone who has ever watched plexity, and using it to build models that describe the
cells enter anaphase can testify) the inhibition is lifted next level of complexity’. Thus, he claims that ‘systems
when all the chromosomes are properly aligned on the biology is an approach, not a field’. The more we learn
metaphase plate, such that it looks as though someone about the complexity of the regulatory network con-
fired a starting pistol (figure 1) to signal chromosome trolling cell proliferation the more useful are the
separation. systems biology approaches in the cell cycle field.
Pines & Hagan [17] revisit many of the points raised The final contribution to this collection by Kronja &
in the preceding articles from a wide-ranging pers- Orr-Weaver [19] covers one of the less familiar areas of
pective, but they go on to stress the importance of cell cycle control, namely the control of expression of
intensely local conditions controlling physically distant mRNA at the level of translation. It turns out that
processes. A particular concern of theirs is the spindle there is quite a lot to say, not only in the authors’ favour-
pole in fission yeast and its role as the place where a com- ite model system, the Drosophila egg, zygote and early
mitment to mitosis is made first, and the centrosome in embryo, but also in yeast, frogs and even human cells.
animal cells, which they argue plays a central role in the It has been known for some time that translation of
control of mitotic entry. They make a plea for more normal capped mRNAs declines during mitosis,
quantitative studies in cell biology, and urge the develop- whereas internal ribosome entry sites (IRES) are prefer-
ment of reporters that can monitor the local activity of entially used, and some of the important examples of
protein kinases and phosphatases in living cells. this switch have recently come to light; their underpro-
Hyman’s article [18] takes up the same theme from duction causes faults in cytokinesis. The majority of
a ‘systems biology’ perspective. Actually, one of his well-established and better worked-out examples do
main concerns is people’s understanding of exactly come from eggs and early embryos, however, which is
what is systems biology. Tony makes the important probably not surprising considering that transcriptional
point that both time and space cover vast ranges of control of gene expression is largely absent in these
scale in biology. Molecular movements in proteins (typically) enormous cells. The regulatory networks
occur on the microsecond timescale, yet it takes are quite complicated, as can be seen from figure 2 of
years for a human to reach sexual maturity. Or look this review. One suspects that there is rather a lot to be
at Barford’s beautiful pictures of the APC/C elsewhere learned still in this area.
in this issue and remind yourself that a human on Altogether, this collection of articles provides a
the same scale would be roughly twice as big as the kind of partial snapshot of the current state of under-
Earth. Hyman makes the same plea as Pines and standing in some of the most active areas of enquiry in
Hagan: more emphasis on quantitative data is the broad field of the cell cycle. For the most part, the
Phil. Trans. R. Soc. B (2011)
 Introduction. The cell cycle T. Hunt et al. 3497

general principles are reasonably well defined, but the chromosome segregation through growth-related
precise details of molecular mechanism in many cases kinases and phosphatases. Phil. Trans. R. Soc. B 366,
prove harder to pin down than perhaps one might have 3508–3520. (doi:10.1098/rstb.2011.0124)
expected 25 years ago. Moreover, there remain con- 6 Mazia, D. 1961 Mitosis and the physiology of cell
division. In The cell, vol. III (eds J. Brachet & A. E.
siderable tracts of uncharted territory, that is, areas
Mirsky), pp. 77–413. New York, NY: Academic Press.
where even the basic principles are difficult to compre- 7 van Werven, F. J. & Amon, A. 2011 Regulation of
hend. First and foremost among these is the problem entry into gametogenesis. Phil. Trans. R. Soc. B 366,
of the regulation and coordination of cell growth, 3521–3531. (doi:10.1098/rstb.2011.0081)
and the relationship between growth control and div- 8 Cross, F. R., Buchler, N. E. & Skotheim, J. M. 2011
ision control, which was arguably the starting point Evolution of networks and sequences in eukaryotic cell
when Paul Nurse decided to work on fission yeast cycle control. Phil. Trans. R. Soc. B 366, 3532–3544.
with the late Murdoch Mitchison. It is perhaps appro- (doi:10.1098/rstb.2011.0078)
priate to end with an acknowledgement of Murdoch’s 9 Diffley, J. F. X. 2011 Quality control in the initiation of
contribution to this field. Apart from definitively defin- eukaryotic DNA replication. Phil. Trans. R. Soc. B 366,
ing the field in the title of his 1971 monograph ‘The 3545–3553. (doi:10.1098/rstb.2011.0073)
10 Labib, K. & De Piccoli, G. 2011 Surviving chromosome
Biology of the Cell Cycle’ [20] (the term was not in
replication: the many roles of the S-phase checkpoint
common currency before this, surprisingly enough), pathway. Phil. Trans. R. Soc. B 366, 3554–3561.
Murdoch served as a stimulating, quizzical, generous (doi:10.1098/rstb.2011.0071)
mentor to Paul Nurse as well as two of the editors of 11 Langerak, P. & Russell, P. 2011 Regulatory networks
this issue, Kim Nasmyth and Bela Novak. Murdoch integrating cell cycle control with DNA damage check-
took a keen interest in the cell cycle field until the points and double-strand break repair. Phil.
very end, and his passing marks the end of an exciting Trans. R. Soc. B 366, 3562–3571. (doi:10.1098/rstb.
and heroic era. 2011.0070)
12 Stern, B. & Nurse, P. 1996 A quantitative model for the
cdc2 control of S phase and mitosis in fission yeast.
Trends Genet. 12, 345– 350. (doi:10.1016/S0168-9525
Tim Hunt1, Kim Nasmyth2 and
(96)80016-3)
Béla Novák2,* 2011 13 Uhlmann, F., Bouchoux, C. & López-Avilés, S. 2011 A
1 quantitative model for cyclin-dependent kinase control
Cancer Research UK, Clare Hall Laboratories,
South Mimms, Herts EN6 3LD, UK of the cell cycle: revisited. Phil. Trans. R. Soc. B 366,
2
Oxford Centre for Integrative Systems Biology, 3572 –3583. (doi:10.1098/rstb.2011.0082)
14 Domingo-Sasanes, M. R., Kapuy, O., Hunt, T. & Novak,
Department of Biochemistry, University of Oxford, South
B. 2011 Switches and latches: a biochemical tug-of-war
Parks Road, Oxford OX1 3QU, UK between the kinases and phosphatases that control mitosis.
*Author for correspondence (bela.novak@bioch.ox. Phil. Trans. R. Soc. B 366, 3584–3594. (doi:10.1098/rstb.
ac.uk). 2011.0087)
15 Musacchio, A. 2011 Spindle assembly checkpoint: the
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