Cell Cycle - ms2016asab.files.wordpress.com€¦ · the cell cycle machinery, frequently via the induction of Cdk inhibitors. Suppression of cdk activity 1. Inhibitory phosphorylation

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