Synopsis of cell cycle

Sayan Karmakar
A 2015 collection on Cytology

Self-reproduction is perhaps the most fundamental character of cells for all living organisms. All cells
reproduce by dividing into two, with each parent cell giving rise to two daughter cells on completion of each
cycle of cell division. These newly formed daughter cells can themselves grow and divide, giving rise to
a new cell population formed by the growth and division of a single parent cell and its progeny. The
orderly distribution of duplicated chromosomes in a mother cell to its daughter cell is the essence of
mitosis. In the simplest case, such cycle of cell growth and division allow a single bacterium to form a
colony consisting of millions of progeny cells during overnight incubation on a plate of nutrient agar
medium. In a more complex case, repeated cycles of cell growth and division result in the development
of a single fertilized egg into the approx. 1014 cells that make up the human body.

The term cell cycle refers to the ordered series of events that lead to cell division and the
production of two daughter cells, each containing chromosomes identical to those of the parent
cell.

The division of all cells must be carefully regulated and coordinated with both cell growth and DNA
replication in order to ensure the formation of progeny cells containing intact genomes. In eukaryotic
cells, progression through the cell cycle is controlled by a series of protein kinases that have been
conserved from yeasts to mammals. In higher eukaryotes, this cell machinery is itself regulated by the
growth factors that control cell proliferation, allowing the division of individual cells to be coordinated
with the needs of the organism as a whole. Not surprisingly, the defects in the cell cycle regulation are
of common cause of the abnormal proliferation of cancer cells, so studies of the cell cycle and cancer
have become closely interconnected.

The division cycle of most cells consists of 4 coordinated processes : cell growth, DNA replication,
distribution of the duplicated chromosomes to daughter cells and cell division. The distribution of the duplicated
chromosomes to the daughter cells is organized and executed by microtubules, which are components
of the cytoskeleton. These fibres composed of proteins called tubulins, attach to the chromosomes and
move them about within the dividing mother cell. During mitosis, the microtubules assemble in a
complex array called the spindle. The formation of the spindle is associated with microtubule
organizing centres (MTOCs), which are found in the cytoplasm of eukaryotic cells, usually neat the
nucleus. In animal cells, the MTOCs are differentiated into small organelles called centrosomes. In
plant cells, MTOCs that do not have distinct centrosomes define these poles and establish the mitotic
spindle. In bacteria, cell growth and DNA replication takes place throughout most of the cell cycle and
duplicated chromosomes are distributed to daughter cells in association with the plasma membrane.
However, in eukaryotes, the cell cycle is more complex and consists of 4 discrete phases. Although cell
growth is usually a continuous process, DNA is synthesized during only one phase of the cell cycle,
and the replicated chromosomes are then distributed to daughter nuclei by a complex series of events
preceding the cell division. In addition to duplicating their genome, In addition to duplicating their
genome, most cells also duplicate their other organelles and macromolecules; otherwise, they would
get smaller with each division. To maintain their size, dividing cells must coordinate their growth (i.e.,
their increase in cell mass) with their division; it is still not clear how this coordination is achieved.

Cells Are Irreversibly Committed to Cell Division at a Cell Cycle Point Called START : In most
eukaryotic cells, the key decision of whether or not a cell will divide is made at the point of whether or
not to enter S phase. In most cases, once a cell has become committed to entering the cell cycle, it must
complete it. START defines a stage in G1 after which cells are irreversibly committed to the cell cycle.
Molecularly, it is defined as the point when G1/S phase CDK activity reaches levels sufficient to
initiate S phase. Extracellular signals such as nutritional state (in yeast) and the presence of mitogens
and anti-mitogens (in vertebrates) regulate entry into the cell cycle.
High accuracy and fidelity are required to ensure that DNA replication is carried out correctly and that
each daughter cell inherits the correct number and order of each chromosome. To achieve this,
progression between these stages of cell cycle is controlled by a conserved regulatory apparatus or cell-
cycle control system or checkpoint pathways which not only coordinates the different events of the
cell cycle but also links the cell cycle with extracellular signals that control cell proliferation.
Checkpoint pathways prevent initiation of each step in cell division until earlier steps on which it
depends have been completed and mistakes that occurred during the process have been corrected. The
core of this system is an ordered series of biochemical switches that initiate the main events of the cell
cycle, including chromosome duplication and segregation. In most cells, additional layers of regulation
enhance the fidelity of the cell division and allow the control system to respond to various signals from
both inside and outside the cell. The master controllers of the cell cycle are a small number of
heterodimeric protein kinases that contain a regulatory subunit (cyclin) and a catalytic subunit
(cyclin-dependent kinase, CDK). Today, we know that the activity of the key proteins that promote
cell cycle progression, the CDK’s, fluctuate during the cell cycle. These heterodimeric kinases regulate
the activation of multiple proteins involved in entry into the cell cycle, DNA replication, and mitosis
by phosphorylating them at specific regulatory sites, activating some and inhibiting others to coordinate
their activities. These oscillations in CDK activity are a fundamental aspect of eukaryotic cell cell cycle
control. Regulated degradation of proteins also plays a prominent role in important cell cycle
transition. Since protein degradation is irreversible, this ensures that the process move in only one
direction through the cell cycle.
Actually the oscillations are generated by positive feedback mechanisms, where specific CDK’s
promote their own activation. These positive feedback loops are coupled to subsequent negative
feedback mechanisms where, indirectly or with a built-in delay, CDK’s promote their own
inactivation. Oscillators not only propel the cell cycle forward but also create abrupt transitions
between different cell cycle states, which is essential to bring about distinct cell cycle states. Laid on the
cell cycle oscillator machinery is a system of surveillance mechanisms that further ensures that the next
cell cycle event is not activated before the preceding one has been completed or before errors that
occurred during the preceding steps are corrected. These surveillance mechanisms are called
Checkpoint Pathways. This system is so efficient, a mis-segregation event occurs only once in 104-103
divisions. These multiple layers of control put on the cell cycle control machinery ensure that the cell
cycle is robust and error free.
Inside the cell, the control system monitors progression through the cell cycle and delays later events
until earlier events have been completed. The control system also monitors the outside the cell. In a
multicellular animal, the system is highly responsive to the signals from other cells, stimulating cell
divisions when more cells are needed and blocking it when they are not. The cell cycle control system
therefore has a central role in regulating cell numbers in the tissues of the body. Mutations that
inactivate or alter the normal operation of the checkpoint pathways contribute to the generation of
cancer cells because they result in chromosomal rearrangements and abnormal numbers of
chromosomes, which lead to further mutations and changes in gene expression level that cause
uncontrolled cell growth.
Appropriately, Hartwell, Hunt and Nurse were awarded the Nobel Prize in Physiology and Medicine in
2001 for the initial experiments that elucidated the master regulators of cell division in all eukaryotes.

Cyclins and CDKs : Nomenclature and the roles in the mammalian cell cycle
Cyclin-dependent
Cyclin Function General Name
kinase (CDK)
Mitotic CDKs
CDK 1 Cyclin A, Cyclin B Mitosis (Maturation Promoting
Factor, MPF)
Entry into the cell cycle G1/S phase CDK
CDK 2 Cyclin E, Cyclin A
S-phase S phase CDK
G1
CDK 4 Cyclin D G1 CDKs
Entry into the cell cycle
G1
CDK 6 Cyclin D G1 CDKs
Entry into the cell cycle
KEY CONCEPTS ON Regulation of CDK Activity :
 Cyclin-dependent kinases are activated by cyclin subunits. Their activity is controlled at
multiple levels.
 Different cyclin subunits activate
CDKs at different cell cycle
stages. Cyclins are present only
in the cell cycle stages that they
promote.
 Protein degradation is the key
mechanism responsible for
restricting cyclins to the
appropriate cell cycle stage. This
degradation is mediated by the
ubiquitin-proteasome system
and the ubiquitin ligases APC/C
and SCF. Fluctuation of MPF activity and cyclin concentration
 Activating and inhibitory during the cell cycle
phosphorylation on the CDK
subunit contributes to the regulation of CDK activity. CDK inhibitors (CKIs) inhibit CDK
activity by directly binding to the cyclin-CDK complex.
 CDKs initiate every aspect of each cell cycle stage by phosphorylating many different target
proteins. Systematic efforts using protein kinases engineered to bind only modified forms of
ATP have led to the identification of
many of these substrates.

Unicellular organisms tend to grow and divide

as fast as they can, and their rate of
proliferation depends largely on the availability
of nutrients in the environment. The cells of a
multicellular organism, however, divide only
when the organism needs more cells. Thus for
an animal cell to proliferate, it must receive
stimulatory extracellular signals, in the form of
mitogens, from other cells, usually its
neighbours. Mitogens overcome intracellular
braking mechanisms that block progress
through the cell cycle.

Cells at different stages of the cell cycle can be

distinguished by the DNA content. In G1, the
cells are diploid (containing two copies of each chromosome), so their DNA content is referred to as 2c
(c designates the haploid DNA content of the genome). During S-phase, replication increases the DNA
content of the cell from 2c to 4c, so cells in S-phase gave DNA contents ranging from 2c to 4c. DNA
content then remains at 4c for cells in G2 and M, decreasing to 2c after cytokinesis. Experimentally,
cellular DNA content can be determined by incubation of cells with a fluorescent dye that binds to
DNA, followed by analysis of the fluorescence intensity of the individual cells in a flow cytometer or
fluorescence-activated cell sorter, thereby distinguishing and allowing isolation of the cells in the G 1, S
and G2/M phases of the cell cycle.
FEATURES OF THE CELL CYCLE
Stage Major Features
G0 phase Stable, non-dividing period of variable length

Interphase

G1 phase Growth and development of the cell; G1/S checkpoint

S phase Synthesis of DNA

G2 phase Preparation for division; G2/M checkpoint

M phase

Prophase Chromosomes condense and mitotic spindle forms

Prometaphase Nuclear envelope disintegrates and spindle microtubules anchor to kinetochores

Metaphase Chromosomes align on the spindle-assembly checkpoint

Anaphase Sister chromatids separate, becoming individual chromosomes that migrate

towards the spindle poles

Telophase Chromosomes arrive at spindle poles, the nuclear envelope reforms and the
condensed chromosomes relax

Cytokinesis Cytoplasm divides; cell wall forms in plant cells

When microorganisms are cultivated in liquid medium, they usually are grown in a
batch culture or closed system— that is, they are incubated in a closed culture vessel
with a single batch of medium. Because no fresh medium is provided during
incubation, nutrient concentrations decline and concentrations of wastes increase.
The growth of microorganisms reproducing by binary fission can be plotted as the
logarithm of the number of viable cells versus the incubation time.