Cell cycle CONTROL

 

Strict cell cycle regulation is vital to ensure faithful segregation of genetic material and survival of organisms. Proper regulation of cell cycle allows normal development and maintenance of  multicellular organisms including plants and animals.Failure to coordinate such regulation processes leads to genome instability, often associated with birth defects and cancer. Such regulations are of two types namely control point regulation and check point regulation. 

 

Cell cycle checkpoints: Cell cycle checkpoints are control mechanisms that ensure the fidelity of cell division in eukaryotic cells. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase. Checkpoints occur throughout the cell cycle. It control the orderly progress of cell through the cell cycle, which prevent one stage from proceeding unless necessary earlier stages have been completed.Checkpoints assess the readines of the cell to proceed on the pathway.Each checkpoint represents a control loop that makes the initiation of one event in the cell cycle  dependent on the successful completion of an earlier event. A checkpoint works by acting directly on the factors that control progression through the cell cycle. In plants three  major checkpoints have been found.

 

i. INTRA S-PHASE CHECK POINT:  It is also known as DNA replication checkpoint, which ensures that mitosis is not initiated until DNA replication is complete and also that no DNA is replicated twice.

 

ii. SPINDLE ASSEMBLY CHECK POINT: The Spindle Assembly Checkpoint (SAC) delays anaphase onset until all chromosomes are properly attached to the mitotic spindle

 

iii. SPINDLE POSITION CHECK POINT: It ensures all chromosomes are properly segregated to daughter cells before the telophase and cytokinesis.

 

In addition with this another  check point is also noted, which is called,

                

iv. DNA DAMAGE CHECK POINT: The DNA damage checkpoint, arrests cells in G1, S phase, G2 or even mitosis in case of DNA lesions

 

Control Mechanism of  Cell cycle:Leland Hartwell discovered a specific class of gene that control the cell cycle. One of these gene is called ‘Start’.It has central role in controlling the first step in each cell cycle. He also introduced the concept of ‘check points’. At a check point a cell can be arrested if previous events have not been completed.Later Paul Nurse identified, cloned and characterized one of the key regulator of the cell cycle called Cdk (Cyclic Dependent Kinase). Cdk was highly conserved during evolution.Timothy Hunt has discovered cyclin protein that regulate the Cdk function. Thus regulation of cell cycle is actually the activation and systematic activity of cyclins and Cdk.

 

                                      At two critical points a kinase enzyme combines with a cyclin and this moves  the cell forward.Some cells,divide continuously throughout the life of the organism. Other cells,are arrested in the G1 phase.If the nucleus from one of these cells is placed in cytoplasm of S-phase cell, it starts to finish the cell cycle. Many biologists, have shown that the activity is due to the enzymes, called Cyclin-dependent kinases (Cdks).It regulates the passage of cells through the checkpoints of cell cycle.In respect of enzymology a Kinase is an enzyme that removes a phosphate group from ATP and adds it to another protein. The phosphorylated molecule, which may also be a kinase, is again activate other protein-kinase . Activation by kinases is evidently a common way by which the cell can turn on various metabolic pathways.

 

                                          There are two types of kinases-S-kinase and M-kinase.S-kinase is capable of starting the process of DNA replication after it has combined with S-cyclin. S-cyclin is now destroyed and S-kinase is no longer active. M-kinase is capable of turning on mitosis after it has combined with M-cyclin It is known that this particular kinase starts the process of (i) chromosome condensation, (ii) nuclear envelope breakdown, and (iii) Spindle assembly. Then the  M-cyclin is destroyed. Its destruction is responsible for inactivating M-phase kinase and releasing the daughter cells to leave mitosis.M-phase kinases are reversible,and its phosphorylation is required for the reorganization of the cell into a mitotic spindle, and dephosphorylation of the same substrates is required to return to an interphase organization.

 

The activity of these kinases rises and falls as the cell progresses through the cycle. The oscillations lead directly to cyclical changes in the phosphorylation of intracellular proteins that initiate or regulate the major events of the cell cycle-DNA replication, mitosis and cytokinesis. Cyclical changes in Cdk activity are controlled by a complex array of enzymes and other proteins. The most important of these Cdk regulators are proteins known as cyclins C  as their name implies, are dependent on cyclins for their activity.Cell cycle progression depends on discrete control points. There are two points at which a decision may be taken on whether to proceed through another cell cycle or not.

 

(a) Commitment to chromosome replication in G1 Phase: The commitment point in yeast and many plant cells is called Start and in animal cells it is called the restriction point.

 

(b) Commitment to mitotic division at the end of G 2: If the cell does not divide at this point then the cell will have twice the normal complement of chromosomes.

 

                         In majority cells, G1 control is the major point of decision and G2/M control is subsidiary. Cells spend the longest part of  their cycle in G1, and it is the length of G1 that is adjusted in response to growth conditions.In the diploid organisms these cells usually likely to be called upon to divide again, e.g., nuclei at some stages of insect embryogenesis divide and crest in the tetraploid state. In the haploid organisms, it is more common for cells to rest in G2, this provide some protection against damage to DNA, since there are two copies of the genome instead of the single copy present in G1. Some yeasts can use either G1 or G2 as the primary control point, depending on the nutritional conditions. Some (haploid) mosses usually use G2 as the control point. 

 

                          The G1 phase of the cycle is the most variable phase, both in duration and in the variety of extemal and internal controls over cell division Nutritional status, growth factors, the density of the cell population, and the developmental state of the cell all affect the length of G1 and whether the cell will pass the restriction point or Start point and divide A cell that does not pass the restriction point will diverge from the cell cycle, temporarily or permanently as a non dividing G0 cell. If all other conditions favour cell division, the cel will proceed through the restriction point when it grows enough to achieve a certain volume to genome ratio This cell is now irreversibly committed to divide. It duplicates its chromosomes in the S phase and continues to grow in the G2 phase, the last period of interphase.

 

                              The transition from interphase to mitosis (M- phase) requires a threshold concentration of MPF.Actually a molecular clock system synchronizes the steps of cell cycle on the basis of interaction of cdk. Cyclin and MPF.The cell cycle has a divide/don’t-divide decision point (restriction point or start point) and a control system that choreographs division once the cell is committed to reproduce and these two occur through the  molecular clock system.The phases of molecular clock system are as follows:

 

(1) Cyclins synthesized throughout the cell cycle and accumulate during early interphase (G1 phase). Cyclins prepare the chromosome for replication

(2) Increase of S-phase promoting factor (SPF) leads the cell entry into S-phase and duplicates the DNA as well as centrioles.

(3) The cyclin associates with another protein, cdc2, to form active MPF.

(4) MPF functions as a protein kinase -triggering the activation_of_numerous

proteins that facilitate mitosis. M-phase promoting factor causes assembly of mitotic spindle, breakdown of nuclear envelope and sharpening of chromosomes.

(5) Activation of anaphase-promoting factor (APF) causes sister chromatids to separate and move toward poles.

(6) One of the proteins activated by MPF is an enzyme that brings MPF activity to a halt by degrading cyclin

(7) Since the cyclin degrading enzyme is only active in the presence of MPF, it ceases to function as it destroys cyclin.Thus M-phase cyclins get destroyed.

(8) The cdc2 component of MPF is recycled, and, back to step (1), i.e.synthesis of new cyclin leads to another peak of Synthesis of G1- cyclins and MPF activity for the next cycle.