Cell Cycle Regulation and Checkpoints: Proteins and Inhibitors

Cell Cycle Regulation and Checkpoints: Proteins and Inhibitors

To divide and duplicate is one of the fundamental properties of cells. The growth and development of all organisms are dependent upon Cell Cycle Regulation and Checkpoints: Proteins and Inhibitors and the enlargement and division of their cells. All sexually reproducing multicellular organisms begin their life from a single cell, the zygote, and it is the multiplication of its descendants which results in the growth of the organism.

The human body, for example, comprises some 10,000,000,000,000 cells, all of which are derived from the zygote. In unicellular organisms, on the other hand, cell division helps in reproduction during which two or more individuals arise from the mother cell. Since new cells always arise from the pre-existing ones, there have to be some means of their multiplication. The process through which this is achieved is called cell division

There are two major types of cell divisions mitosis and meiosis. Each of these is divided into two events-nuclear division (Karyokinesis), which is followed by the division of the cytoplasm (Cytokinesis).

Cell Cycle Regulation and Checkpoints:

In a population of dividing cells whether inside the body or in a culture dish, each cell passes through a series of defined stages that constitute the cell cycle. The cell cycle comprises essentially two periods; the interphase (Period of non-apparent division) and the period of division. The division may take place by mitosis, meiosis or other mechanisms of cell replication. cells spend most of their lifespan in interphase, which is a period of intense biosynthetic activity in which the cell doubles in size and duplicates its chromosome complement.

The cell cycle can be considered a complex phenomenon by which cellular material is divided equally into daughter cells.

The cell cycle is divided into four successive stages or intervals:

1. ‘G₁’  2. ‘S’ phase   3. ‘G₂¹ and. 4. ‘M’ or mitosis phase.

Interphase: The doubling of DNA takes place during this period. Synthesis of DNA occurs in the restricted portion of interphase-the so-called ‘S’ period, i.e. synthetic period, which is preceded and followed by two “gap” periods of interphase (G₁ and G₂) in which there is no DNA synthesis.

The duration of the Cell Cycle Regulation and Checkpoints varies greatly from one type of cell to another; for a mammalian cell growing in culture with a generation time of 16 hrs., the different periods would be as follows: G₁ = 5 hrs.; S = 7 hrs.; G₂=3 hrs.; and mitosis = 1 hr.

“G,’ phase

It is also called the pre-DNA synthetic period or post-mitotic phase which is the most variable in length depending on the physiologic condition of the cells. During this stage, cells regain normal shape, size and content by transcription of rRNA, tRNA, m RNA and synthesis of different types of proteins. It occupies near about 18% time of the cell cycle.

*S’ phase

During this phase synthesis i.e. replication and duplication of chromosomal DNA molecules are completed. Thus each chromosome now carries a duplicate set of genes. Each chromosome is now composed of two sister chromatids which are held together by a common centromere, even various enzymes and proteins are synthesized and so the name. It occupies approximately 50% of the time of the cell cycle.

*G,’ phase

It is also called as pre-mitotic phase or the phase between the end of DNA synthesis and the start of mitosis. During the G₂ phase, a cell contains a double amount (4n) of DNA present in the original diploid cell (2n). In this, all metabolic activities concerned the growth of cytoplasm and its constituent organelles and macromolecules are performed; so that cells show little growth and increase in size. It occupies approximately 25% of the time of the cell cycle.

‘M’ phase

‘M’ phase is also referred to as the mitotic phase of Cell Cycle Regulation and Checkpoints, during which the mother cell divides and gives rise to daughter cells and occupies 7% of the time of the cell cycle.

The regulation of the duration of the cell cycle occurs primarily by arresting it at a specific point of G₁, and the cell in the arrested condition is said to be in Go state. In the Go state, the cell may be considered to be withdrawn from the cell cycle; when conditions change and growth is resumed, the cell re-enters the G₁ period.

 MITOSIS

Mitosis is an equational division that is divided into 4 phases

1 Prophase 

2. Metaphase 

3. Anaphase

. Telophase

1) Prophase

This phase of mitosis is of the longest duration. It may also be called the Disorganization phase. The centriole and the centrosphere divide. The two centrioles, each surrounded by the centrosphere, move towards opposite ends or poles of the cell.

Nuclear changes: The fine chromatid threads shorten and thicken due to spiralization (coiling like wire springs) and dehydration. They are now called chromosomes. Each chromosome has a small, rounded, clear and non-staining granule called the centromere.

2. Metaphase:

The disappearance of the nuclear membrane is followed by the appearance of numerous fine fibrils, which extend as a spindle between the two centrioles. , The chromosomes, each consisting of two chromatids attached to a centromere, move towards the equatorial plane, i.e. the plane midway between the two poles of the cell.

3. Anaphase:

Each centromere divides to separate the two chromatids, now called chromosomes, which move apart and migrate towards the opposite poles. Their movement is caused by the contraction and shortening of the spindle fibres.

4. Telophase

This is the reorganization phase, resulting in the constitution of two daughter nuclei. The chromosomes in each pole undergo despiralization (uncoiling) and hydration and become long thin threads that form a network, the chromatin reticulum. Side by side, a nuclear membrane appears around each set of chromatin threads, leaving the centriole outside it.

Cytokinesis

Division of cytoplasm starts during the late telophase. Constriction or cleavage furrow appears in the equatorial region and gradually deepens, finally pinching off the cell into two parts. Each part contains a daughter nucleus and is called a daughter cell.

3.3 MEIOSIS

Meiosis is a type of cell division, which reduces chromosome number to half by reduction division. As this cell division occurs in gonads during reproduction and results in the formation of gametes, hence it is also called gametogenic division.

It consists of  (I) Meiosis – I Which is a modified prophase and achieves the mixing of the maternal and paternal sets of genes (instructions). (II) Meiosis II – It is modified only by the omission of its S-phase, ensuring the reduction down to the haploid content of DNA.

Meiosis I

It is composed of Karyokinesis which in turn is divided into four successive stages

a. Prophase I,   b. Metaphase – I,   c. Anaphase-I.  d. Telophase – I

a. Prophase I

This phase of meiosis is of the longest duration. For the convenience of study, it has been distinguished into five sub-stages:

1. Leptotene  2. Zygotene  3. Pachytene  4. Diplotene,  5. Likeness.

1. Leptotene stage (leptos-thin, nema-thread)

The stage marks the beginning of meiotic division. The chromatin material condenses to form fine, long threads of the chromosomes.

2. Zygotene stage (zygon-adjoing)

This stage is also called the stage of “mating thread”, where the chromosomes shorten and thicken and the homologous chromosomes (Maternal and Paternal) pair up. It is now referred to as the two-strand stage. The pairing of the homologous chromosomes is known as synapsis.

3. Pachytene stage (Pachus-thick)

It is the largest stage, which begins when synapsis is completed. The members of a synaptic pair coil around each other touching at one or more homologous points. The points of contact are known a Chiasmata (singular, chiasma). A chromosome pair forming a synopsis is called a diad or a bivalent.

4. Diplotene

 The bivalent pair begin to separate and each is seen to consist of two chromatids. The chromatids of a chromosome cross each other at some points which are called Chiasmata. At this point, the genetic material of homologous chromosomes is mutually exchanged or reshuffled. This phenomenon of mutual exchange of genetic material is called “crossing over”, which has very great importance in heredity.

5. Diakinesis

The chromosomes continue to shorten and thicken. The centriole and centrosphere divide and move towards opposite poles. Each centriole is surrounded by aster rays. The nuclear membrane disappears. The nucleolus, which was till now attached to a specific diad, detaches from it and disappears.

b. Metaphase-I

As in mitosis, a spindle of fine fibrils appears between the two centrioles. The bivalent chromosomes move towards the equatorial region.

c. Anaphase – I

This is the migratory phase. The centromeres of homologous chromosomes (bivalent) move towards opposite poles.

d. Telophase-I

It is the reorganization phase. Half the partners of bivalent chromosomes form one nucleus with a nuclear membrane and the other half form the other nucleus.

Cytokinesis may or may not follow nuclear division. After short interphase, each haploid daughter cell enters the second meiotic division.

Meiosis – II

It is more or less mitotic division but here DNA does not duplicate but two centromere divides; which help in dividing each of the two haploid daughter cells into similar haploid daughter cells.

a. Prophase-II

The centriole and two centrospheres divide and move towards opposite poles, each surrounded by aster rays. The nucleolus and nuclear membrane disappear. Each centromere still has two chromatids attached to it.

b. Metaphase – II

Spindle fibres appear between the two centrioles and two centromeres get attached to them at the equatorial plane. This plane is at right angles to the equatorial plane of the first meiosis division.

c. Anaphase-II

Each centromere divides and separates the two chromatids which now called chromosomes, migrate

towards opposite poles, just as in mitosis.

d. Telophase-II

At each pole, a haploid nucleus is reorganized. A nuclear membrane and nucleolus are formed, two spindle and asters disappear, and the cell constricts to form two daughter cells, each with a haploid number of chromosomes. This second division is a mitotic division.

PROTEINS INVOLVED IN CELL CYCLE:

The mechanism of cell cycle regulation depends upon specific proteins like Cyclins and CDK’s.

1) CDK

Cyclin-dependent kinases are a type of serine/threonine kinase which are activated by cyclins to drive the progress of the cell cycle. There be 12 different CDK genes, but only 5 are used to control the cell cycle. These are CDK-1, CDK-2, CDK-3, CDK-4, and CDK-6.

2) Cyclin Activatory kinase-

Cyclin Activatory kinase adds phosphate to CDK1, CDK2, CDK4 and CDK6.

3) CDK- inhibitory kinase

It consists of wee 1 kinase which is responsible for the regulation of the G2/M checkpoint. It negatively regulates entry into mitosis by catalyzing inhibitory tyrosine phosphorylation of the Cdc2/cyclin B kinase complex.

4) Activatory phosphatase-

It is also known as CDC-25 Activatory phosphatase. It removes the inhibitory phosphate group which is present on the 16th amino acid.

5) Ubiquitin ligase-

Ubiquitin is a small protein that consists of a specific sequence of 76 amino acids. It is also known as E3 ligase which suppresses and degrades the misfolded protein. F box complex is also known as SCF complex is a type of Ubiquitin ligase- which can be seen in S- phase.

6) Inhibitory protein-

INK4 and CIP/KIP two is an inhibitory protein that inhibits CDK4/6 (cell cycle arrest at G1 phase of the cell cycle)  and CDK-2 (cell cycle arrest at S-phase of the cell cycle)  activity.

DIFFERENT TYPES OF CHECKPOINTS IN CELL CYCLE:

There are three checkpoints in a cell cycle.

(1)  G1 checkpoint (restriction checkpoint)

G1 checkpoint is additionally referred to as a restriction point. G1 checkpoint operates at the cease of the G1 phase of the cell cycle. It tests the DNA for any injury before it is going for a cycle of DNA replication in the next section (S phase). If DNA injury is detected, then Inhibition of cyclin/CDK complex is formed which stops the development of the cell cycle. The cells are then directed to the DNA repair mechanism to rectify the DNA damage. If the environmental conditions are not good, the cell may additionally enter into the G0 phase.

(2) G2 checkpoint (G2-M DNA Damage Checkpoint)

The 2nd checkpoint is G2 which operates at the end of the G2 phase. It can also be referred to as a G2-M DNA damage checkpoint. G2 checkpoint assesses the DNA for any damage during the DNA replication in the previous phase  (S phase). G2 checkpoint moreover ensures that the complete DNA has been replicated.

(3) Metaphase (M)-checkpoint (Spindle meeting checkpoint)

It is also called a spindle assembly checkpoint. It works at the end of the M phase. Metaphase checkpoint checks the spindle apparatus in the cell. For the normal segregation of chromosomes, the correct arrangement of chromosomes at the metaphase plate is important. This checkpoint prevents cells from incorrectly placing or sorting the chromosomes during the process of cell division and thus this checkpoint is important.

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