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Transcript
Main text Introduction Mitosis (Gk. Mitos – warp thread or fiber and osis – act, process) is a type of equational division in which chromosomes replicate and become equally distributed among the two daughter nuclei. Mitosis was first observed in plant cells by Strasburger in 1870 and in animal cells by Boveri and W. Flemming in 1879. The term ‘mitosis’ was introduced by Flemming in 1882 as chromatin of the cell nucleus appears as long threads in the first stage. It is the usual method of cell division in all eukaryotic organisms. It is characterized typically by resolving the chromatin of the nucleus into a threadlike form which condenses into chromosomes, each of which separates longitudinally into two parts called chromatids, each of which is retained in each of two new cells resulting from the original cell. The development of an individual from zygote to adult stage takes through mitotic cell divisions and it is the most common method of division which brings about growth in multicellular organisms, and increase in population of unicellular organisms. Although growth also takes place through increase in cell size, but when cell size increases, surface area of cell does not increase in the same proportion as the cell volume. Therefore, cell division helps in growth also by way of increasing surface area of the cell. Thus, mitosis is a necessity for the maintenance and perpetuation of life. One of the basic requirements of cell division meant for growth would be that it should give rise to two daughter cells, which should resemble each other and also the parent cell qualitatively and quantitatively. Since a cell also has to maintain continuity from one generation to another, and since the heredity material within the chromosomes has to copy itself most faithfully, a cell has to divide in growing tissue and elsewhere in such a manner that the two daughter cells are similar to each other and resemble the parent cell from which these were produced. However, in divisions taking place in sex cells, the daughter cells may differ from one another and also from parent cells, but they would still have most of the essential features in common. The basic outline of cell division in all the living organisms is almost the same which for the sake of convenience of description is divided into different phases constituting what is called as the cell cycle. Cell cycle Cell cycle can broadly be divided into interphase and mitosis. In the interphase, the cell prepares materially for the division and the mitosis (M phase) is the main cell division phase, where the cell actually divides into two. Interphase: Preparation for Mitosis Interphase is the phase of the cell-cycle in which the cell spends the majority of its time and performs the majority of its purposes, including preparation for cell division. In this preparation, the cell increases its size and makes a copy of its DNA, the centrioles divide, and proteins are actively produced. Interphase is also considered to be the 'living' phase of the cell, in which the cell obtains nutrients, grows, reads its DNA, and conducts other "normal" cell functions. The majority of eukaryotic cells spend most of their time in interphase. Interphase does not describe a cell that is merely resting but is rather an active preparation for cell division. The interphase is divided into following 3 sub stages: G1 (Growth 1 or Gap 1) phase It is the phase, in which the cell grows and functions normally. During this time, much protein synthesis occurs and the cell grows (to about double its original size) more organelles are produced, increasing the volume of the cytoplasm. The DNA in a G1 diploid eukaryotic cell is 2N, meaning that there are two sets of chromosomes present in the cell. Haploid organisms, such as some yeast will be 1n and thus have only one copy of each chromosome present. A cell may pause in the G1 phase before entering the S phase and enter a state of dormancy called the G0 phase (discussed latter). Most mammalian cells of nerve and muscle tissue systems do this. In order to divide, the cell re-enters the cycle in ‘S’ phase. There is a "restriction point" present at the end of G1 phase. This point is a series of safeguards to ensure that the DNA is intact and no repairment is required, and that the cell is functioning normally. Functionally, the safeguards exist as proteins known as cyclin-dependent kinases (CDKs), called as S-phase promoting factor (SPF) or G1/S phase checkpoint and will be discussed latter. The G1 CDK proteins activate the transcription factors for a variety of genes. These include genes which are responsible for DNA synthesis proteins and S phase CDK proteins. S-Phase (Synthetic phase) During this phase, the synthesis of DNA (via semiconservative replication) and other preparations for main cell division take place. The DNA is the ‘brain’ of the cell; hence the cell will need to copy its DNA faithfully in order to pass it on to two daughter cells. At the beginning of the S stage, each chromosome is composed of one coiled DNA double helix molecule. The enzyme DNA helicase splits the DNA double helix and DNA polymerase start, attaching complementary base pairs to the DNA strand, making two new semi-conservative strands. At the end of this stage, each chromosome has two identical DNA double helix molecules and, therefore, is composed of two sister chromatids which remain joined at the centromere. During S phase, the centrosome is also duplicated. The end result is the duplication of genetic material in the cell, which will eventually be divided into two. Damage to DNA often takes place during this phase, and DNA repair is initiated following the completion of replication. Incomplete or poor DNA repair may flag cell cycle checkpoints, which halts the cell cycle. However, after the cell has completed this phase, it is very likely that the cell will continue on to complete the cell cycle. G2 (Growth 2 or Gap 2) Phase It is the phase in which cell undergoes a period of rapid growth in preparation for mitosis. It is the last stage of cell cycle up to which nucleus is well defined bounded by nuclear membrane and with nucleolus. Chromosomes although replicated are in the form loosely packed chromatin fibers. As in G1 phase, at the end of this phase too is a control check point called G2/M- checkpoint. G0 Phase As discussed above in G1 phase, some cells that do not divide often or ever, enter a stage called G0 (Gap zero), which is either a stage separate from interphase or an extended G1 phase, which follows the restriction point, a cell cycle checkpoint found at the end of G1. In this phase, cells exist in a quiescent state. This is sometimes referred to as a "post-mitotic" state, since cells in G0 phase are in a non-dividing phase outside of the cell cycle. Some types of cells, such as nerve and heart muscle cells, become post-mitotic when they reach maturity (i.e., when they are terminally differentiated) but continue to perform their main functions for the rest of the organism's life. Multinucleated muscle cells that do not undergo cytokinesis are also often considered to be in the G0 stage. On occasions, a distinction in terms is made between a G0 cell and a 'post-mitotic' cell (e.g., heart muscle cells and neurons), which will never enter the G1 phase, whereas other G0 cells may enter. Cells enter the G0 phase from a cell cycle checkpoint in the G1 phase, such as the ‘Restriction point’ (animal cells) or the ‘START’ point (yeast). This usually occurs in response to lack of growth factors or nutrients. During the G0 phase, the cell cycle machinery is dismantled and cyclins and cyclin-dependent kinases disappear. Cells then remain in the G0 phase until there is a reason for them to divide. Some cell types in mature organisms, such as parenchymal cells of the liver and kidney, enter the G0 phase semi-permanently and can be induced to begin dividing again only under very specific circumstances. Other types of cells, such as epithelial cells, continue to divide throughout an organism's life and rarely enter G0. Although many cells in the G0 phase may die along with the organism, not all cells that enter the G0 phase are destined to die; this is often simply a consequence of the cell's lacking any stimulation to reenter in the cell cycle. The term "post-mitotic" is sometimes used to refer not only to quiescent cells (like those in G0) but also to senescent cells. Cellular senescence is distinct because it is a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable. Senescence then, unlike quiescence, is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis. At any given time, most of the cells in an animal’s body are in G0 phase; however some cells among them, like liver cells can resume G1 phase in response to factors released during injury. Cell cycle duration The duration of various phase of cell cycle vary from organism to organism and even in different tissues of the same organism. Cells in growing animal embryos can complete their cell cycle in less than 20 minutes; the shortest known animal nuclear division cycle occurs in fruit fly (Drosophila) embryos (8 minutes). Most cells of adult mammals spend about 20 hours in interphase, this account for about 90% of the total time involved in cell division. However generally if we assume the cell cycle of a particular cell to be of 24 hours, more than 23 hours of it will be consumed in interphase and only less than one hour will it spent in Mitosis or M phase. For example mouse L cells dividing for every twenty four hours spent 12 hours in G1 phase, 6-8 hours in S phase; 3-6 hours in G2 phase and only 1 hour in M phase; similarly cells of Vicia faba (Broad beans) spent 12 hours in G1 Phase, 6 hours in S phase, 12 hours in G2 phase and 1 hour in M phase. Some cells such as certain cells in human liver have cell cycles lasting more than a year. Mitosis or M-Phase The onset of M-phase is allowed by the formation of the mitotic cyclin-Cdk complex known as M phase promoting factor that occurs as a cell cycle regulatory mechanism in the G2 phase. The primary result of mitosis is the transferring of the parent cell's genome into two daughter cells. The genome is composed of a number chromosomes-complexes of of tightly-coiled DNA that contain genetic information vital for proper cell function. The mitosis or M phase of the cell cycle although a continuous process is for the sake of convenience and understanding divided into following sub-phases. Preprophase In plant cells only, prophase is preceded by a preprophase stage. In highly vacuolated plant cells, the nucleus has to migrate into the center of the cell before mitosis can begin. This is achieved through the formation of a phragmosome - a transverse sheet of cytoplasm that bisects the cell along the future plane of cell division. In addition to phragmosome formation, preprophase is characterized by the formation of a ring of microtubules and actin filaments (called preprophase band) underneath the plasma membrane around the equatorial plane of the future mitotic spindle. This band marks the position where the cell will eventually divide. The cells of higher plants (such as the flowering plants) lack centrioles; instead, microtubules form a spindle on the surface of the nucleus and are then being organized into a spindle by the chromosomes themselves, after the nuclear membrane breaks down. The preprophase band disappears during nuclear envelope dissolution and spindle formation in prometaphase. Prophase At the beginning of the prophase the nucleus of the cell becomes spheroid, viscosity of the cytoplasm increases and the chromatin fibers start condensing and thinning to Chromosomes take the become shape coiled, of chromosomes. shortened and more distinct as the prophase progresses. This shortening and thickening of chromosomes is due to two reasons: (1) coming together of scaffolding or axial proteins and (2) lateral looping and coiling of chromatin fibers which is assisted by a category of proteins called condensins. At the early prophase the chromosomes are evenly distributed in the nucleus. As the prophase progresses chromosomes begin the to align themselves to the periphery of the nucleus creating a clear central area. Chromosomes continue shortening and thickening to assume the characteristic shape and size, which is necessary for their equitable distribution latter. An important and characteristic feature of the prophase is longitudinal splitting of the each chromosome into two sister chromatids which remain attached to each other only at centromere. In the late prophase chromatids at the centromere will get attached with the spindle fibers with the help of kinetochore. The nucleolus and nuclear membrane (with some exceptions) start disappearing. The centrosomes which are the organizing centre of microtubules begin to separate to opposite poles of the cell in the form of asters (centrioles and microtubule astral rays). However spindle poles are organized without asters in plant cells which lack centrioles. Prometaphase The major event marking the cell’s entry to prometaphase is the breakdown of the nuclear envelope into small vesicles. Kinetochores (a proteinous structure at the centromere region of the sister chromatids) become fully matured on the centromeres of the chromosomes. Distinction between cytoplasm and nucleoplasm fades and the organelles like Endoplasmic Reticulum (ER) and Golgi apparatus disorganize. The segregation of the replicated chromosomes is brought about by a complex cytoskeltal machine with many moving parts- the mitotic spindle. It is constructed from microtubules (tubulin dimers) and their associated proteins, which both pull the daughter chromosomes towards the poles of the spindle and move the poles apart. Both the assembly and the function of the mitotic spindle depend on microtubule-dependent motor proteins. These proteins belong to two families- the kinesin-related proteins, which usually move toward the plus end of the microtubules, and the dyneins, which move towards the minus end. In the mitotic spindle, motor proteins operate at or near the ends of the microtubules. These ends are not only sites of microtubule assembly and disassembly; they are also sites of force production. The assembly and dynamics of the mitotic spindle rely on the shifting balance between opposing motor plus-end- proteins. directed Microtubules and minus-end-directed emerging from the centrosomes at the poles of the spindle reach the chromosomes. The attachment of the chromosomes with the spindle is a dynamic process. It seems to involve a search and capture mechanism, in which microtubules radiated from each of the rapidly separating centrosomes grow outside toward the chromosomes. Microtubules that attach to a centromere become stabilized, so that they no longer undergo catastrophes. They eventually end up attached end-on at the kinetochore (a complex protein machine that assembles onto the highly condensed DNA at the centromere during late prophase). The end-on attachment to the kinetochore is through the plus end of the microtubules, which is now called a kinetochore microtubule. In the spindle, some microtubules extend from one pole to the centre of the cell, where their ends overlap with the ends of other microtubules that extend from the opposite end of the spindle. The two sets together, overlapping in the centre form a large framework. Other microtubules run from a pole to a centromere. Each end of the spindle is attached to one of the two faces of the centromere at kinetochore on each chromosome. About 15 to 35 microtubules attach to each kinetochore. The role of prometaphase is completed when all of the kinetochore microtubules have attached to their kinetochores, unattached upon which kinetochore, metaphase and thus a begins. An non-aligned chromosome, even when most of the other chromosomes have lined up, will trigger the spindle checkpoint signal. This prevents premature progression into anaphase by inhibiting the anaphase-promoting complex until all kinetochores are attached and all the chromosomes aligned. Metaphase Once the chromosomes get captured by the microtubules of the spindle, the microtubules push and pull on the chromosomes, gradually aligning them to the cell centre or spindle equator forming what is called as Metaphase plate. This alignment is due to the counterbalance of the pulling powers generated by opposing kinetochores Mitotic cells usually spend about half of M phase in metaphase, with the chromosomes aligned on the metaphase plate, jostling about, awaiting the signal that induces sister chromatids to separate to begin anaphase. Treatment with drugs that destabilize microtubules, such as colchicine or vinblastine arrests mitosis for hours or even days. This observation led to the identification of a spindle attachment check-point which is activated by the drug treatment and arrests progress in mitosis. The checkpoint mechanism is used by the cell cycle control system to ensure that the cells do not enter anaphase until all chromosomes are attached to both poles of the spindle. If one of the protein components of the checkpoint mechanism is inactivated by mutation or by an intracellular injection of antibodies against the component, the cells initiate anaphase permanently. The spindle attachment checkpoint monitors the attachment of the chromosomes to the mitotic spindle. It is thought to detect either unattached kinetochores or kinetochores that are not under the tension that results from bipolar attachment. In either case attached kinetochore emit a signal that delays anaphase until they all are properly attached to the spindle. Drugs that destabilize microtubules prevent such attachment and therefore maintain the signal and delay the anaphase. Anaphase When every kinetochore is attached to a cluster of microtubules and the chromosomes have lined up along the metaphase plate, the cell proceeds to anaphase (from the Greek ανα meaning “up,” “against,” “back,” or “re-”). Entrance into anaphase is triggered by the inactivation of M phase-promoting factor that follows mitotic cyclin degradation. During anaphase, the kinetochore microtubules retract, increasing the separation of the sister chromatids as they are moved further toward the opposite spindle poles. Anaphase can be subdivided into two distinct phases. In the first phase, called Anaphase A, chromosomes move pole ward, away from the metaphase plate with the retraction of the microtubules. This movement occurs at approximately 2 micrometers per minute (the entire length of a cell is between 10 and 30 micrometers). In the second phase, or Anaphase B, the mitotic poles marked by the centrosomes themselves separate by the elongation of a specific type of nonkinetochore microtubule, called a polar microtubule. The extent of the separation of the poles varies from species to species. The entire duration of anaphase is relatively short, usually only lasting a few minutes. As if following a neatly choreographed dance, the sister chromatids separate, rapidly moving toward the pole to which their microtubule is attached. The cell appears "stretched" as the spindle fibers slide past one another, elongating the spindle apparatus and further separating the poles. Shortening of the microtubules by removal of tubulin units pulls the chromosomes closer and closer to the pole. The movement of sister chromatids to opposite sides of the cell completes the equal division and distribution of genetic material. Agents that inhibit microtubules depolymerization, such as deuterium oxide, also inhibit chromosome movement, where as those that speed depolymerization such as low level of colchicines, speed movement. The amount of energy necessary to move a chromosome from the metaphase plate to the end of the spindle is small; just 20 ATP molecules are sufficient. Long chromosomes may tangle somewhat, but microtubules exert sufficient pull to untangle them and drag them to the ends of the spindle. Because the spindle is shaped like a football, as chromosomes on each side get closer to the end, they are pulled together into a compact space. Chromatids separate from each other with the breakdown of the cohesion linkage the protein complex that binds the sister chromatids at the metaphase plate. This metaphase-to-anaphase transition is triggered by the activation of the anaphase promoting complex (APC) or cyclosome APC. The APC is a complex of several proteins. APC cohesion. directly When all triggers the the degradation kinetochores are of properly attached with the microtubules in the metaphase, the APC becomes active. The activated APC then targets securin for degradation. Degradation of securin allows a cysteine protease called separase to cleave chromosome bound cohesion allowing anaphase onset. Once this proteolytic complex is activated, it has at least two crucial functions: (1) it cleaves and deactivates the M-phase cyclin (M-cyclin) thereby inactivating M-Cdk; and (2) it cleaves inhibitory securing, thereby activating the separase. Separase then cleaves a subunit in the cohesion complex to unglue the sister chromatids. The sister chromatids immediately separate- and are now called daughter chromosomes- and move to opposite poles. Telophase In telophase (Gk telos-end, phase-stage), the spindle apparatus disintegrate as the microtubules are broken down into tubulin monomers that can be used to construct the cytoskeletons of the daughter cells. Fragment of nuclear envelope appear near around each set of sister chromatids which can chromosomes, complete now be connect nuclear called with envelope each other around and each form set of chromosomes. The chromosomes again start uncoiling into more loose threads of chromatin, which enable them for gene expression. It is not known how new nuclear pores are formed. Gradually, new nucleoli appear as the ribosomal genes become active and produce ribosome subunits. The spindle depolymerizes completely and disappears. Most of the events in telophase are reversal of those in prophase. Cytokinesis Cytokinesis, from the Greek cyto- (cell) and kinesis (motion, movement) is the process in which the cell actually divides into two. With the two nuclei already at opposite poles of the cell, the cell cytoplasm separates, and the cell pinches in the middle, ultimately leading to cleavage. Cytokinesis is often mistakenly thought to be the final part of telophase; however, cytokinesis is a separate process that begins simultaneously with telophase. Cytokinesis is technically not even a phase of mitosis, but rather a separate process, necessary for completing cell division. In animal cells, a cleavage furrow (pinch) containing a contractile develops ring where the metaphase plate used to be, pinching off the separated nuclei. During different proliferative divisions, animal cell cytokinesis begins shortly after the onset of sister chromatid separation in the anaphase of mitosis. A contractile ring, made up of myosin II and actin filaments, assembles in the middle of the cell. Myosin II uses the free energy released when ATP is hydrolyzed to move along these actin filaments, constricting the cell membrane to form a cleavage furrow. Continued hydrolysis causes this cleavage furrow to move inwards. Ingression continues until a so-called midbody structure is formed and the process of abscission then physically cleaves this midbody into two. In both animal and plant cells, cell division is also driven by vesicles derived from the Golgi apparatus, which move along microtubules to the middle of the cell In plant cell, due to the presence of a cell wall; cytokinesis is significantly different from that in animal cells. Rather than forming a contractile ring, plant cells construct a cell plate in the middle of the cell. The Golgi apparatus releases vesicles containing cell wall materials. These vesicles fuse at the equatorial plane and form a cell plate. The cell plate begins as a fusion tube network, which then becomes a tubulo-vesicular network (TVN) as more components are added. The TVN develops into a tubular network, which then becomes a fenestrated sheet which adheres to the existing plasma membrane. Cell cycle control and checkpoints Leland Hartwell (born 1939), of HCRC, USA, was awarded noble prize in medical physiology in 2001for his discoveries of a specific class of genes that control the cell cycle. One of these genes called "start" was found to have a central role in controlling the first step of each cell cycle. Hartwell also introduced the concept "checkpoint", a valuable aid to understanding the cell cycle. We know that cell cycle involves the synthesis and division of DNA- the genetic material of the cell, which directly or indirectly controls all the activities and future course of action of the new formed cells. Therefore it becomes very important for the cell cycle to repair all the possible errors which can occur during S phase in DNA before the nuclear division so that the faulty DNA can be prevented from proliferation. For that matter, the cell has developed very efficient system of controls in form of cell cycle checkpoints. These checkpoints are also necessary because, the synthesis of DNA and separation of chromatids are irreversible processes and need to be examined before happening. The cell cycle checkpoints put it on hold at specific points so that the processes can be assayed for accuracy and halted in case of any error. A cell uses three checkpoints during the whole processes at specific points in the cell cycle to access the accuracy and to integrate the external and internal signals before its transition to next phase. The passage through these checkpoints is controlled by cyclin dependent serine/threonine kinases, kinase which (CDK) regulate family cell of cycle progression through phosphorylation of proteins that function at specific phases of the cell cycle. These kinase were discovered by Paul Nurse at different phases of the cell cycle and their activity is each dependent on association with a member of the cyclin family of regulatory sub-units. These kinases are therefore called as cyclin dependent kinases or Cdks. The checkpoints are discussed as below: G1/S checkpoint: This is the first checkpoint where a cell in response to surroundings can decide whether to divide or not. The possible factors which govern this checkpoint include growth factors, nutritional status of the cell and the fitness of the genome. Poor nutritional status, lack of growth factors and damaged DNA can halt the cell cycle at this point. This checkpoint has been well studied in yeast where it is being termed as ‘START’. In animals it is termed as ‘restriction point’. G2/M checkpoint: This is the second and most important checkpoint which is meant for assessment of DNA which has been synthesized in S phase. This checkpoint is commonly referred to as Mitosis Promoting Factor (MPF). The G2 checkpoint provides an opportunity for repair of damaged DNA if any, hence stopping the proliferation of damaged cells therefore help to maintain genomic stability. Passage through represents the commitment to mitosis. this checkpoint Any substance which damages DNA can cause the cycle to stop at this point. Spindle checkpoint at late metaphase: this checkpoint comes into action just before the partition of two sets of chromosome destined for two daughter cells at metaphase. The second irreversible step in cell cycle is the segregation of chromatids during anaphase; hence the Spindle checkpoint ensures that all the chromosomes are attached to spindle fibers correctly before transition into anaphase. Molecular mechanism of Cell cycle controls The primary molecular mechanism of the cell cycle control is due to the phosphorylation (addition of Phosphate) and dephosphorylation (removal of phosphate) of proteins. The enzymes which bring about phosphorylation are called as kinases and those which bring about dephosphorylation are called as phosphatases. The phosphorylation of a protein can activate or inactivate a protein depending upon the protein. Similarly the protein inactivated by phosphorylation can be activated by dephosphorylation and vice versa. As discussed above the enzymes which carryout phosphorylation of proteins are cyclin dependent kinases (Cdks) which in combination bring about the phosphorylation of a variety of cellular proteins thereby controlling the different stage of the cell cycle. The most important Cdk was isolated in fission yeast and was named as cdc2. It has now become clear that the cdc2 kinase is controlled by phosphorylation, and a specific cyclin associated with it. Phosphorylation of cdc2 at one site activates it and phosphorylation at another site deactivates it. Similarly cdc2 can combine with different cyclins at different stages of cell cycle. Thus the signal to start the cycle at one point comes with the combining of cdc2 with one cyclin and the signal at another stage of the cycle comes by joining of the cdc2 with another cyclin. The exact molecular mechanisms of Cdk control are still not well established.