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GREAT EXPERIMENTS
Cell cycle genes
Lee Hartwell
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Introduction
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The cell cycle is the process by which a
cell duplicates its contents and divides them into two daughter cells.
It has been apparent for more than a hundred years that there is an
order to the events of the cell cycle. Chromosome duplication must
precede chromosome segregation, which, in turn, must precede
cytokinesis. The cell cycle was initially divided into two phases,
based on what could be seen through a microscope: interphase, when
chromosomes could not be seen, and mitosis, when they visibly condensed
and segregated. It was not until radioactive thymidine was used to
study DNA replication in the early 1950s that the current four-phase
cycle of G1, S, G2, and M was defined. DNA replication occurred in S
phase and chromosome segregation in M. G1 and G2 were "gaps" between
these events. By the middle of the 1960s, it became clear that the
decision to initiate a cell cycle was controlled in G1, suggesting that
the control of cell division was distinct from the events of cell
division. What was missing were ways of finding out how the events
within the cell cycle were coordinated, and of identifying the
molecular components that ordered these events. I decided to take a
genetic approach, with the ultimate goal of identifying genes that
functioned at discrete steps of the cell cycle.
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Background
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I became interested in cell division when
I was a postdoctoral fellow with Renato Dulbecco. I was fascinated by
the differences between normal and cancerous cells that were evident
even in cells removed from the body and grown in culture. My decision
to use genetics to study the problem in yeast grew out of frustration.
I had spent over a year in Dulbecco's laboratory trying to develop a
project on cell division utilizing mammalian cells, but each of the
approaches that I tried failed.
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My desire to apply genetics to the
problem was strongly influenced by my experience as an undergraduate at
Cal Tech. There I had the wonderful experience of working with Bob
Edgar when he began using temperature-sensitive (ts) and
nonsense mutants to define all of the genes of the virus T4. Over a few
years, he and Bill Wood used these mutants to work out the complicated
process of building the T4 virus structure. There was no way this could
have been done without genetics. Mutants revealed the incomplete
intermediates of morphogenesis, and cell extracts from mutant-infected
bacteria provided the starting materials for in vitro
morphogenesis experiments. I wanted to be able to do something equally
definitive with cell division. I thought that genetics would be ideally
suited to studying cell division because, in several fundamental
respects, cell division was like phage reproduction. In both cases, DNA
replication was followed by a series of macromolecular assemblies that
built chromosomes. In phage, this was followed by phage particle
assembly, and in cells, by formation of the mitotic spindle and the
cytokinetic apparatus. It seemed reasonable to expect that mutants
could be used to reveal the pathway of morphogenetic events leading to
cell division, much as they had been for phage reproduction.
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Figure 1
A scanning electron micrograph of a number of Saccharomyces cerevisiae cells. Many of the cells have buds, which differ in size from cell to cell. Photo courtesy of Ira Herskowitz.
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Figure 2
The bud grows continuously as the sequence of events
that replicates and separates the chromosomes takes place. Major cell
cycle events that can be assayed are indicated.
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Genetic studies with mammalian cells were
impossible, so Dan Wulff, a colleague of mine, suggested finding a
model eukaryotic cell amenable to genetic analysis. A casual perusal of
the journal Genetics revealed many elegant studies with the yeast
Saccharomyces cerevisiae, which is shown in Figure 1.
At that time, yeast geneticists were preoccupied with genetic
recombination, and most of the published work was about that
phenomenon. However, Howard Douglas and Dan Hawthorne had also done
some nice work on the genetics of gene regulation with the galactose
pathway. Overall, S. cerevisiae looked ideal for my purposes.
It grew mitotically as either a haploid or a diploid, which meant that
one could isolate recessive mutants in the haploid phase and use the
diploid phase to place them in complementation groups. It also grew as
single cells, unlike most other fungi. A third advantage I did not
appreciate until much later: S. cerevisiae is a budding
yeast, and each new cell grows from a bud on the parent cell. Because
the bud grows continuously over the course of the cell cycle, the size
of the bud reflects the position of the cell within the cycle. This is
shown in Figure 2.
Bud size proved to be a key morphological marker that made the
recognition and analysis of cell cycle mutants very easy. The cell
cycle in yeast was also known to be similar to those in larger
eukaryotes. C. F. Robinow had shown that yeast has a mitotic spindle
and well-defined spindle poles (2989), and Don Williamson
had demonstrated that S. cerevisiae had a cell cycle with
the classic G1, S, G2, and M phases (2990).
Before I could begin working with yeast, however, I needed some
instruction, so I made a short visit to two of the leading yeast
genetics labs, those of Bob Mortimer and Herschel Roman, after which I
enthusiastically decided to work with yeast.
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Based on the phage T4 paradigm, I
isolated over 400 temperature-sensitive mutants and studied the
patterns of macromolecular synthesis and cell division following a
shift from permissive to restrictive temperature. A subset had patterns
suggesting specific defects in protein synthesis, RNA synthesis, DNA
synthesis, or cell division (2992). The ultimate goal, of
course, was to identify proteins that function in cell physiology, but
the current approach to this problem, gene cloning, had not even been
conceived of. Showing that one could go from mutant to protein was
essential to validating the project. Fortunately, by this time Calvin
McLaughlin, an expert in protein synthesis, had arrived at UC Irvine,
where I was a faculty member at the time. Together we studied the
protein synthesis mutants and were able to identify two genes as the
structural genes for aminoacyl-tRNA synthetases (2993).
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The experiments
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Our survey of macromolecular synthesis
and cell division in the temperature-sensitive mutants had identified
some with the properties we expected for cell cycle mutants. That is,
after a shift from permissive to restrictive temperature, cell division
stopped while DNA, RNA, and protein synthesis continued. However, this
criterion was not very precise and did not discriminate between blocks
at different phases of the cell cycle. The key breakthrough that opened
up the cell cycle to genetic analysis was the realization that cell
cycle progression could be studied very conveniently by time-lapse
photomicroscopy. This insight came quite serendipitously. Brian Reid,
an undergraduate in the laboratory, was studying some mutants that
formed elongated shapes and it made sense to analyze them by
photomicroscopy. As soon as we started looking at the photographs, we
realized how informative they were for studying cell division. This was
because S. cerevisiae grows by budding; since the bud grows
continuously throughout the cell cycle, simply looking at the size of
the bud revealed where a cell was in the cycle.
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Figure 3
Cell cycle mutants can be identified visually by
following a population of cells over time after the temperature is
raised. A population of normal cells or cells that are mutant in
non?cell cycle functions will always contain cells at all stages of the
cycle. The cells in a population of a cell cycle mutant, however, will
accumulate at one stage of the cycle. Such a population is easily
identified because all the cells will have the same shape.
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We screened through hundreds of our ts
mutants and discovered that about ten percent of them appeared to have
a specific block in the cell cycle. That is, when a population of cells
was shifted from the permissive temperature at which they could
reproduce to the restrictive temperature where they could not, all of
the cells stopped at one stage of the cycle for example, with a small
bud. The process is shown in Figure 3.
We were insecure about whether the external morphology of the cells
alone was telling us the whole story, so Joe Culotti, a graduate
student, learned how to stain nuclei, and analyzed the nuclear
morphologies as well. His findings were consistent with cell cycle
defects in that the nuclei were also uniformly arrested in each mutant
population.
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Figure 4
Normal cells and three cdc mutants after several hours at the restrictive temperature.
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Our initial screen identified thirty-five cell cycle genes (2038).
The phenotypes of mutants in several of them are shown in Figure 4.
To study them, we developed methods for rapidly synchronizing cultures
of mutant cells so that we could follow events after a shift to the
restrictive temperature. In order to determine the specific defect in
each mutant, we needed to be able to monitor as many of the events of
the cell cycle as possible. We developed assays for budding, DNA
replication, nuclear division, cytokinesis, and growth in the overall
size of the cell. Breck Byers became interested in the mutants and
added several parameters that at the time could only be monitored by
electron microscopy: spindle pole duplication, separation, and
segregation, as well as spindle elongation (2994).
Within the initial set of 35 genes, we found blocks specific to every one of these events.
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Figure 5
Analysis of many cdc mutants produced this
branched pathway describing the interdependencies among events in the
cell cycle of yeast. Any event downstream of another is dependent on
it; events in the different branches are independent of one another.
Cytokinesis depends on all the other events, but reinitiation of the
cell cycle is independent of cytokinesis. The numbers indicate the
point at which the corresponding cdc mutation blocks a branch.
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The phenotypes of the mutants revealed a
pathway of cell cycle events in which downstream events were dependent
on completion of some but not all upstream events. For example, cells
that did not bud still replicated their DNA and completed nuclear
division, showing that the nuclear cycle was independent of the cycle
of budding, cytokinesis, and cell division. However, mutants that
failed to replicate DNA did not complete nuclear division or cell
division, demonstrating a dependence of these events on one another. We
used two additional methods to confirm and extend this pathway. First,
we made double mutants between all mutants with different phenotypes.
For example, two mutants failed to initiate DNA replication but they
differed in budding — one (cdc7) arrested with a large bud
and the other (cdc4) continued budding for multiple cell cycles.
The double mutant (cdc7, cdc4) budded for multiple cell cycles,
suggesting that the cdc4 step preceded the cdc7 step.
We also used a series of shifts between temperature and inhibitors to order steps.
As shown in Figure 5, the result was a picture of the cell cycle as a relatively simple
pathway of dependent events leading to cell division. The pathway was
composed of many sequential, gene-controlled steps, with genes assigned
to every event that we had been able to assay. These included spindle
pole body enlargement, duplication, and separation; initiation of DNA
replication; DNA elongation; three stages of nuclear division;
cytokinesis; and cell separation (824).
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One gene in the cell cycle drew special attention, CDC28.
It was the first gene in the pathway, and neither budding nor DNA
replication could occur if it did not function. Second, it functioned
at the stage at which growth was integrated with division. That is, if
growth was abruptly prevented by withdrawal of nitrogen (or other
nutrients), cells that had started the cycle by producing a bud
continued until they completed the cycle, even though there was no
growth (2995). Small cells produced during nutrient starvation
were arrested before the step controlled by CDC28, and when nutrients
were replaced, the tiny cells grew in size and did not complete the CDC28
step until they reached normal size. Moreover, cell division was controlled during
mating at the very same step (2996; 2997; 2998; 2999).
Haploid yeast cells come in two different types (called mating types)
and mate by fusing with a cell of the opposite type. During this
process, the cell cycles of the two cells must be synchronized. To
achieve this, each cell type secretes a pheromone that arrests the cell
cycle of cells of the opposite type. We mimicked the process
experimentally by adding purified pheromone to cells of the responsive
mating type, and found that this arrest also occurs at the CDC28-controlled step.
Stimulated by the central role of the CDC28
gene, Steve Reed, a postdoc in my lab, and Kim Nasmyth, a postdoc in
Ben Hall's lab, collaborated to clone the gene, the first cell cycle
gene cloned by functional complementation (3001). When Steve
later sequenced it in his own laboratory, he inferred that it encoded a
protein kinase, which ultimately proved to be the cyclin-dependent
kinase (3003).
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The legacy
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Understanding the role of the
cyclin-dependent kinase as the major controlling element of the cell
cycle came from a convergence of several lines of research in different
laboratories. Most notable was the elegant and seminal work of Paul
Nurse working on the cdc2 gene of Schizosaccharomyces pombe
(see The discovery of as the key regulator of the cell cycle).
A long history of studies on the maturation-promoting factor (MPF) from
the frog Xenopus laevis, and Tim Hunt's discovery of the periodic
synthesis and decay of cyclin also provided key insights. The CDC28
gene from S. cerevisiae was shown to be the budding yeast homologue of the S. pombe cdc2
gene and to encode one of the two proteins that make up MPF. The
historical development of these insights has been reviewed in detail (3004).
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For me, what is most instructive about
the cell cycle field for understanding how science progresses comes
from analyzing the assumptions and motivations driving each of these
three areas of work. As I noted above, the genetic analysis of the S. cerevisiae
cycle was driven by the paradigm of phage morphogenesis and yielded a
view of the cell cycle entirely consistent with that paradigm. CDC28
only achieved prominence because it was the first gene in the pathway
and functioned at the stage where division was controlled by cell
growth and mating pheromone. CDC2 of S. pombe was
identified as important for an entirely different reason. Paul Nurse
assumed that rate-limiting steps were the most important and focused on
CDC2 because some alleles created cells that divided slower
than normal, while others created cells that divided faster than normal
(3005). Marc Kirschner focused on MPF because it was a clock
that oscillated independently of the cell cycle and appeared to provide
the timing mechanism (1570). Even though all three views are
partly right and partly incomplete, science as a process led all three
quests to the same answer, one that was more encompassing than any of
us had expected.
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The author
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Lee Hartwell is president and director of the Fred Hutchinson Cancer
Research Center in Seattle, as well as professor of genetics at the
University of Washington. He has been on the faculty there since 1968.
He has worked with yeast for more than 35 years and sees it as a model
organism for human biology. His current research focuses on using yeast
to understand how individual organisms of the same species can tolerate
the large amount of genetic variation found in populations, and how
genetic variation affects the susceptibility of humans to disease.
Hartwell was born in Los Angeles and was the first member of his
family to attend college, graduating in 1961 from the California
Institute of Technology. He earned a Ph.D. in 1964 with Boris Magasanik
at MIT, and engaged in postdoctoral work at the Salk Institute with
Renato Dulbecco. He was a member of the faculty of the University of
California at Irvine before moving to the University of Washington.
Hartwell has received many awards, including the 2001 Nobel Prize in Physiology or Medicine.
Lee Hartwell
President & Director
Fred Hutchinson Cancer Research Center
1100 Fairview Ave. N., D1-060
Seattle, WA 98109-1024
E-mail: lhartwel@fhcrc.org
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Last Revised on October 22, 2004
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3004 Nasmyth, K.
(2001).
A prize for proliferation.
Cell 107, 689-701.
PubMed Journal
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824 Hartwell, L., Culotti, J., Pringle, J. R., and Reid, B. J.
(1974).
Genetic control of the cell division cycle in yeast.
Science 183, 46-51.
PubMed
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1570 Gerhart, J., Wu, M., and Kirschner, M.
(1984).
Cell cycle dynamics of an M-phase-specific cytoplasmic factor in Xenopus laevis oocytes and eggs.
J. Cell Biol. 98, 1247-1255.
PubMed
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2038 Hartwell, L. H., Culotti, J., and Reid, B.
(1970).
Genetic control of the cell-division cycle in yeast. I. Detection of mutants.
Proc. Natl. Acad. Sci. USA 66, 352-359.
PubMed
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2989 Robinow, C. F. and Marak, J.
(1966).
A fiber apparatus in the nucleus of the yeast cell.
J. Cell Biol. 29, 129-151.
PubMed
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2990 Williamson, D. H.
(1965).
The timing of deoxyribonucleic acid synthesis in the cell cycle of S. cerevisiae.
J. Cell Biol. 25, 517-528.
PubMed
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2992 Hartwell, L. H.
(1967).
Macromolecule synthesis in temperature-sensitive mutants of yeast.
J. Bacteriol. 93, 1662-1670.
PubMed
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2993 Hartwell, L. H. and McLaughlin, C. S.
(1968).
Mutants of yeast with temperature-sensitive isoleucyl-tRNA synthetases.
Proc. Natl. Acad. Sci. USA 59, 422-428.
PubMed
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2994 Byers, B. and Goetsch, L.
(1975).
Behavior of spindles and spindle plaques in the cell cycle and conjugation of S. cerevisiae.
J. Bacteriol. 124, 511-523.
PubMed
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2995 Johnston, G. C., Pringle, J. R., and Hartwell, L. H.
(1977).
Coordination of growth with cell division in the yeast S. cerevisiae.
Exp. Cell Res. 105, 79-98.
PubMed
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2996 Hereford, L. M. and Hartwell, L. H.
(1974).
Sequential gene function in the initiation of S. cerevisiae DNA synthesis.
J. Mol. Biol. 84, 445-461.
PubMed
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2997 Backing-Throm, E., Duntze, W., Hartwell, L. H., Manney, T.R.
(1973).
Reversible arrest of haploid yeast cells in the initiation of DNA synthesis by a diffusible sex factor.
Exp. Cell Res. 76, 99-110.
PubMed
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2998 Hartwell, L. H.
(1973).
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