Cell Cycle
Trends in Cell Biology
Cell Cycle
The orderly sequence of events by which a cell duplicates its
contents and divides into two Daughter Cells
Activities of a cell from one cell division to the next
The period between two mitotic divisions
Cell Cycle Function
• To replicate DNA – without errors
• To Segregate the duplicated DNA equally
into two daughter cells
Cell Cycle
G1: Gap 1, Varying time
S: DNA synthesis
G2: Gap 2
M: Mitosis
G1 Phase
1. Longest and most variable phase
2. Many genes involved in cell cycle progression are switched off so that the cell cannot initiate a new round of proliferation.
3. This repressive system is called restriction point.
4. Antiproliferative stimulus or lack of nutrients diverts the cell to terminal differentiation. Hence cells exit the G1 phase of cell cycle and enter G0.
5. If appropriate positive stimuli are received cells overcome the restriction point and trigger gene expression for a new cycle of DNA replication.
6. Faulty restriction points may lead to uncontrolled proliferation under inappropriate conditions.
7. 6-12 hrs out of 24 hrs, 45 percent
G0 phase
A cell may pause in the G1 phase before entering the S phase and enter a state of dormancy called the G0 phase, in which the cell really do nothing and remains in resting state, Most mammalian cells do this
Cells that are permanently in the G0
phase are called postmitotic cells.
S Phase
• The S phase, is a period in the cell cycle during interphase, between G1 phase and the G2 phase.
• This event is an essential aspect of the cell cycle • Replication of DNA takes place, the amount of DNA in
the cell effectively doubles. • Most of the Histones production occurs during the S
phase . • The duration of S phase is relatively constant among cells of the same species
G2 phase
• Similar to G1, G2 is an intermediate phase, a time for the cell to ensure that it is ready to proceed in the cell cycle.
• This phase occurs between the S phase and m phase
• G2 can be thought of as a safety gap during which a cell can check to make sure that entire of its DNA and other intracellular components have been properly duplicated.
Cell Cycle
The Changes in Cell Components
Cell cycle in-vivo
1. Cell that are highly specialized. Example ????
2. Cell that normally do not divide but can be induced to
begin DNA synthesis and divide when given an
appropriate stimulus. Example ????
3. Cells that normally possess a relatively high level of
mitotic activity. Example ???
The most basic control system should possess the following features:
1. A clock, or timer, that turns on each event at a specific time, thus providing a fixed amount of time for the completion of each event.
2. A mechanism for initiating events in the correct order; entry into mitosis, for example, must always come after DNA replication.
3. A mechanism to ensure that each event is triggered only once per cycle.
4. Binary (on/off) switches that trigger events in a complete, irreversible fashion. It would clearly be disastrous, for example, if events like chromosome condensation or nuclear envelope breakdown were initiated but not completed.
5. Robustness: backup mechanisms to ensure that the cycle can work properly even when parts of the system malfunction.
6. Adaptability, so that the system's behavior can be modified to suit specific cell types or environmental conditions.
Cell Cycle Control System
Cell Cycle Control
The processes of DNA replication and mitosis, and intervening events during the cell cycle, occur in a highly ordered and specific manner.
A complex network of proteins ensures that these events
occur at the proper time.
Cyclin-dependent kinase enzymes (CDKs) associate
successively with different cyclins to determine cell cycle progression.
Regulation of the cell cycle involves steps crucial to the cell,
including detecting and repairing genetic damage, and provision of various checks to prevent uncontrolled cell division.
Cell-Cycle Checkpoints G1 checkpoint In yeast, called start point In animal cells, called restriction point
G2 checkpoint Located at boundary between G2 and M phase Proper completion of DNA synthesis required before cell can initiate
mitosis
Spindle Assembly Checkpoint
Boundary between metaphase and anaphase All chromosomes must be properly attached to these spindle
Information about the completion of cell-cycle events, as well as signals from the environment, can cause the control system to arrest the cycle at specific checkpoints.
Checkpoints in the cell-cycle control system
Checkpoints Generally Operate Through
Negative Intracellular Signals
Negative intracellular signals arrest the cell cycle, rather than
through the removal of positive signals that normally stimulate cell-
cycle progression. Example
Mitotic initiation check point (G2 check point)
Unreplicated DNA inhibits the initiation of mitosis, creating a stop
signal that persists until the completion of DNA replication.
Spindle check point
Each unattached chromosome sends a negative signal to inhibit
progress through the cell cycle., the attachment of the last
chromosome will be easily detected for progress.
Components of Control system
Two key classes of regulatory molecules, cyclins and cyclin dependent kinases (CDKs), control the cell cycle
Cyclins Cyclins are a family of proteins involved in the progression of cells
through the cell cycle
Cyclins regulate cell-cycle progression through interactions with cyclin-
dependent kinases (CDKs)
CDKs Cyclin-dependent kinases (CDK) belong to a group of protein
CDKs are called "cyclin-dependent" because their activity requires
their association with activating subunits called cyclins
Two key components of the cell-cycle control system.
A complex of cyclin with Cdk acts as a protein kinase to trigger
specific cell cycle events. Without cyclin, Cdk is inactive.
(A)In the inactive state, without cyclin bound, the active site is blocked by a
region of the protein called the T-loop (red).
(B)The binding of cyclin causes the T-loop to move out of the active site,
resulting in partial activation of the Cdk2.
(C) Phosphorylation of Cdk2 (by CAK) at T-loop, improving the ability of the
enzyme to bind its protein substrates.
The structural basis of Cdk activation
Molecular mechanisms that regulate Activities of Cdk's
1. Cyclin Binding
Cyclin-cdk complex activates change in active site conformation
Allowing cdk to phosphorylate its substrate
2. Cdk phosphorylation state
Regulated by addition and removal of phosphate groups
A variety of signals act to inhibit cell cycle progression
The effects of inhibitory signals are also mediated by regulators of
the cell cycle machinery, frequently via the induction of Cdk
inhibitors.
Suppression of cdk activity
1. Inhibitory phosphorylation (wee1) primarily in M-phase
2. Cdk Inhibitor proteins (CDKIs) primarily in G1 and S phase
controls
3. Inhibitors of Cell Cycle Progression
The regulation of Cdk activity by inhibitory phosphorylation
CDK Inhibitors
• Except for regulation of cyclin levels, cells develop another
regulatory mechanism of cyclin-CDK complex activity—CdkIs.
• CdkIs bind to cyclin-CDK complexes and inhibit their activity,
which is extremely important once cell cycle enters into
autonomous program, to ensure the fidelity of genetic materials.
•Degradation of sic1 (cdk inhibitor in G1) allows cyclin-cdk to
initiate DNA replication
•Removal of p27 leads to cell cycle progression
The inhibition of a cyclin-Cdk complex by a CKI. The p27 binds to both the cyclin and Cdk in the complex, distorting the active site of the Cdk. Also inserts into the ATP-binding site, further inhibiting the enzyme activity.
4. Controlled proteolysis
Through ubiquitin-proteosome