Жасуша бөліну циклінің сатылары

Series of events and stages that result in cell division

The cell cycle, or cell division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division. In eukaryotic cells (having a cell nucleus) including animal, plant, fungal, and protist cells, the cell cycle is divided into two main stages: interphase, and mitosis in the M phase that also includes cytokinesis. During interphase, the cell grows, accumulating nutrients needed for mitosis, and replicates its DNA and some of its organelles. During the M phase, the replicated chromosomes, organelles, and cytoplasm separate into two new daughter cells. To ensure the proper replication of cellular components and division, there are control mechanisms known as cell cycle checkpoints after each of the key steps of the cycle that determine if the cell can progress to the next phase. In cells without nuclei the prokaryotes, bacteria and archaea, the cell cycle is divided into the B, C, and D periods. The B period extends from the end of cell division to the beginning of DNA replication. DNA replication occurs during the C period. The D period refers to the stage between the end of DNA replication and the splitting of the bacterial cell into two daughter cells. In single celled organisms, a single cell division cycle is how the organism replicates itself. In multicellular organisms such as plants and animals, a series of cell division cycles is how the organism develops from a single celled fertilized egg into a mature organism, and is also the process by which hair, skin, blood cells, and some internal organs are regenerated and healed (with possible exception of nerves; see nerve damage). After cell division, each of the daughter cells begin the interphase of a new cell cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of the cell division.

The eukaryotic cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase (mitosis and cytokinesis). M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's nucleus divides, and cytokinesis, in which the cell's cytoplasm divides forming two daughter cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase. State Phase Abbreviation Description Resting Gap 0 G0 A phase where the cell has left the cycle and has stopped dividing. Interphase Gap 1 G1 Cell growth. The G1 checkpoint ensures that everything is ready for DNA synthesis. Synthesis S DNA replication. Gap 2 G2 Growth and preparation for mitosis. The G2 checkpoint ensures that everything is ready to enter the M (mitosis) phase and divide. Cell division Mitosis M Cell division occurs. The Metaphase Checkpoint ensures that the cell is ready to complete cell division. After cell division, each of the daughter cells begin the interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.

G0 is a resting phase where the cell has left the cycle and has stopped dividing. The cell cycle starts with this phase. Non proliferative (non dividing) cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Some cells enter the G0 phase semi permanently and are considered post mitotic, e. g., some liver, kidney, and stomach cells. Many cells do not enter G0 and continue to divide throughout an organism's life, e. g., epithelial cells. The word "post mitotic" is sometimes used to refer to both quiescent and senescent cells. Cellular senescence occurs in response to DNA damage and external stress and usually constitutes an arrest in G1. Cellular senescence may make a cell's progeny nonviable; it is often a biochemical alternative to the self destruction of such a damaged cell by apoptosis.

Interphase represents the phase between two successive M phases. Interphase is a series of changes that takes place in a newly formed cell and its nucleus before it becomes capable of division again. It is also called preparatory phase or intermitosis. Typically interphase lasts for at least 91% of the total time required for the cell cycle. Interphase proceeds in three stages, G1, S, and G2, followed by the cycle of mitosis and cytokinesis. The cell's nuclear DNA contents are duplicated during S phase.

The ensuing S phase starts when DNA synthesis commences; when it is complete, all of the chromosomes have been replicated, i. e., each chromosome consists of two sister chromatids. Thus, during this phase, the amount of DNA in the cell has doubled, though the ploidy and number of chromosomes are unchanged. Rates of RNA transcription and protein synthesis are very low during this phase. An exception to this is histone production, most of which occurs during the S phase.

G2 phase occurs after DNA replication and is a period of protein synthesis and rapid cell growth to prepare the cell for mitosis. During this phase microtubules begin to reorganize to form a spindle (preprophase). Before proceeding to mitotic phase, cells must be checked at the G2 checkpoint for any DNA damage within the chromosomes. The G2 checkpoint is mainly regulated by the tumor protein p53. If the DNA is damaged, p53 will either repair the DNA or trigger the apoptosis of the cell. If p53 is dysfunctional or mutated, cells with damaged DNA may continue through the cell cycle, leading to the development of cancer.

Mitosis is immediately followed by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle. Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "M phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei in a process called endoreplication. This occurs most notably among the fungi and slime molds, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development. Errors in mitosis can result in cell death through apoptosis or cause mutations that may lead to cancer.

Regulation of the cell cycle involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.

Upon receiving a pro mitotic extracellular signal, G1 cyclin CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome. However, results from a recent study of E2F transcriptional dynamics at the single cell level argue that the role of G1 cyclin CDK activities, in particular cyclin D CDK4/6, is to tune the timing rather than the commitment of cell cycle entry. Active S cyclin CDK complexes phosphorylate proteins that make up the pre replication complexes assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already assembled pre replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's genome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to gene copy number effects, possession of extra copies of certain genes is also deleterious to the daughter cells. Mitotic cyclin CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.

Cyclin D is the first cyclin produced in the cells that enter the cell cycle, in response to extracellular signals (e. g. growth factors). Cyclin D levels stay low in resting cells that are not proliferating. Additionally, CDK4/6 and CDK2 are also inactive because CDK4/6 are bound by INK4 family members (e. g., p16), limiting kinase activity. Meanwhile, CDK2 complexes are inhibited by the CIP/KIP proteins such as p21 and p27, When it is time for a cell to enter the cell cycle, which is triggered by a mitogenic stimuli, levels of cyclin D increase. In response to this trigger, cyclin D binds to existing CDK4/6, forming the active cyclin D CDK4/6 complex. Cyclin D CDK4/6 complexes in turn mono phosphorylates the retinoblastoma susceptibility protein (Rb) to pRb. The un phosphorylated Rb tumour suppressor functions in inducing cell cycle exit and maintaining G0 arrest (senescence). In the last few decades, a model has been widely accepted whereby pRB proteins are inactivated by cyclin D Cdk4/6 mediated phosphorylation. Rb has 14+ potential phosphorylation sites. Cyclin D Cdk 4/6 progressively phosphorylates Rb to hyperphosphorylated state, which triggers dissociation of pRB–E2F complexes, thereby inducing G1/S cell cycle gene expression and progression into S phase. However, scientific observations from a recent study show that Rb is present in three types of isoforms: (1) un phosphorylated Rb in G0 state; (2) mono phosphorylated Rb, also referred to as "hypo phosphorylated' or 'partially' phosphorylated Rb in early G1 state; and (3) inactive hyper phosphorylated Rb in late G1 state. In early G1 cells, mono phosphorylated Rb exits as 14 different isoforms, one of each has distinct E2F binding affinity. and the idea that different mono phosphorylated Rb isoforms have different protein partners was very appealing. A recent report confirmed that mono phosphorylation controls Rb's association with other proteins and generates functional distinct forms of Rb. All different mono phosphorylated Rb isoforms inhibit E2F transcriptional program and are able to arrest cells in G1 phase. Importantly, different mono phosphorylated forms of Rb have distinct transcriptional outputs that are extended beyond E2F regulation. This observation based on the structural analysis of Rb phosphorylation supports that Rb is phosphorylated in a different level through multiple Cyclin Cdk complexes. This also makes feasible the current model of a simultaneous switch like inactivation of all mono phosphorylated Rb isoforms through one type of Rb hyper phosphorylation mechanism. In addition, mutational analysis of the cyclin D Cdk 4/6 specific Rb C terminal helix shows that disruptions of cyclin D Cdk 4/6 binding to Rb prevents Rb phosphorylation, arrests cells in G1, and bolsters Rb's functions in tumor suppressor. Cyclin B cdk1 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, its deactivation causes the cell to exit mitosis. Many human cancers possess the hyper activated Cdk 4/6 activities. Given the observations of cyclin D Cdk 4/6 functions, inhibition of Cdk 4/6 should result in preventing a malignant tumor from proliferating. Consequently, scientists have tried to invent the synthetic Cdk4/6 inhibitor as Cdk4/6 has been characterized to be a therapeutic target for anti tumor effectiveness. Three Cdk4/6 inhibitors – palbociclib, ribociclib, and abemaciclib – currently received FDA approval for clinical use to treat advanced stage or metastatic, hormone receptor positive (HR positive, HR+), HER2 negative (HER2 ) breast cancer. For example, palbociclib is an orally active CDK4/6 inhibitor which has demonstrated improved outcomes for ER positive/HER2 negative advanced breast cancer. The main side effect is neutropenia which can be managed by dose reduction. Cdk4/6 targeted therapy will only treat cancer types where Rb is expressed. Cancer cells with loss of Rb have primary resistance to Cdk4/6 inhibitors.

Current evidence suggests that a semi autonomous transcriptional network acts in concert with the CDK cyclin machinery to regulate the cell cycle. Several gene expression studies in Saccharomyces cerevisiae have identified 800–1200 genes that change expression over the course of the cell cycle. They are transcribed at high levels at specific points in the cell cycle, and remain at lower levels throughout the rest of the cycle. While the set of identified genes differs between studies due to the computational methods and criteria used to identify them, each study indicates that a large portion of yeast genes are temporally regulated. Many periodically expressed genes are driven by transcription factors that are also periodically expressed. One screen of single gene knockouts identified 48 transcription factors (about 20% of all non essential transcription factors) that show cell cycle progression defects. Genome wide studies using high throughput technologies have identified the transcription factors that bind to the promoters of yeast genes, and correlating these findings with temporal expression patterns have allowed the identification of transcription factors that drive phase specific gene expression. The expression profiles of these transcription factors are driven by the transcription factors that peak in the prior phase, and computational models have shown that a CDK autonomous network of these transcription factors is sufficient to produce steady state oscillations in gene expression). Experimental evidence also suggests that gene expression can oscillate with the period seen in dividing wild type cells independently of the CDK machinery. Orlando et al. used microarrays to measure the expression of a set of 1,271 genes that they identified as periodic in both wild type cells and cells lacking all S phase and mitotic cyclins (clb1,2,3,4,5,6). Of the 1,271 genes assayed, 882 continued to be expressed in the cyclin deficient cells at the same time as in the wild type cells, despite the fact that the cyclin deficient cells arrest at the border between G1 and S phase. However, 833 of the genes assayed changed behavior between the wild type and mutant cells, indicating that these genes are likely directly or indirectly regulated by the CDK cyclin machinery. Some genes that continued to be expressed on time in the mutant cells were also expressed at different levels in the mutant and wild type cells. These findings suggest that while the transcriptional network may oscillate independently of the CDK cyclin oscillator, they are coupled in a manner that requires both to ensure the proper timing of cell cycle events. While oscillatory transcription plays a key role in the progression of the yeast cell cycle, the CDK cyclin machinery operates independently in the early embryonic cell cycle. Before the midblastula transition, zygotic transcription does not occur and all needed proteins, such as the B type cyclins, are translated from maternally loaded mRNA.

Analyses of synchronized cultures of Saccharomyces cerevisiae under conditions that prevent DNA replication initiation without delaying cell cycle progression showed that origin licensing decreases the expression of genes with origins near their 3' ends, revealing that downstream origins can regulate the expression of upstream genes. This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression, and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.

Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell cycle. Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of DNA damage. The cell cannot proceed to the next phase until checkpoint requirements have been met. Checkpoints typically consist of a network of regulatory proteins that monitor and dictate the progression of the cell through the different stages of the cell cycle. It is estimated that in normal human cells about 1% of single strand DNA damages are converted to about 50 endogenous DNA double strand breaks per cell per cell cycle. Although such double strand breaks are usually repaired with high fidelity, errors in their repair are considered to contribute significantly to the rate of cancer in humans. While these are the three "main" checkpoints, not all cells have to pass through each of these checkpoints in this order to replicate. Many types of cancer are caused by mutations that allow the cells to speed through the various checkpoints or even skip them altogether. Going from S to M to S phase almost consecutively. Because these cells have lost their checkpoints, any DNA mutations that may have occurred are disregarded and passed on to the daughter cells. This is one reason why cancer cells have a tendency to exponentially acquire mutations. Aside from cancer cells, many fully differentiated cell types no longer replicate so they leave the cell cycle and stay in G0 until their death. Thus removing the need for cellular checkpoints. An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint. Checkpoint regulation plays an important role in an organism's development. In sexual reproduction, when egg fertilization occurs, when the sperm binds to the egg, it releases signalling factors that notify the egg that it has been fertilized. Among other things, this induces the now fertilized oocyte to return from its previously dormant, G0, state back into the cell cycle and on to mitotic replication and division. p53 plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints. In addition to p53, checkpoint regulators are being heavily researched for their roles in cancer growth and proliferation.

Pioneering work by Atsushi Miyawaki and coworkers developed the fluorescent ubiquitination based cell cycle indicator (FUCCI), which enables fluorescence imaging of the cell cycle. Originally, a green fluorescent protein, mAG, was fused to hGem(1/110) and an orange fluorescent protein (mKO2) was fused to hCdt1(30/120). Note, these fusions are fragments that contain a nuclear localization signal and ubiquitination sites for degradation, but are not functional proteins. The green fluorescent protein is made during the S, G2, or M phase and degraded during the G0 or G1 phase, while the orange fluorescent protein is made during the G0 or G1 phase and destroyed during the S, G2, or M phase. A far red and near infrared FUCCI was developed using a cyanobacteria derived fluorescent protein (smURFP) and a bacteriophytochrome derived fluorescent protein (movie found at this link).

A disregulation of the cell cycle components may lead to tumor formation. As mentioned above, when some genes like the cell cycle inhibitors, RB, p53 etc. mutate, they may cause the cell to multiply uncontrollably, forming a tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the proportion of cells that are in active cell division (versus quiescent cells in G0 phase) in tumors is much higher than that in normal tissue. Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same. The cells which are actively undergoing cell cycle are targeted in cancer therapy as the DNA is relatively exposed during cell division and hence susceptible to damage by drugs or radiation. This fact is made use of in cancer treatment; by a process known as debulking, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase (due to increased availability of nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the debulking procedure kills these cells which have newly entered the cell cycle. Non homologous end joining, a less accurate and more mutagenic process for repairing double strand breaks, is active throughout the cell cycle.

The cell cycle must duplicate all cellular constituents and equally partition them into two daughter cells. Many constituents, such as proteins and ribosomes, are produced continuously throughout the cell cycle (except during M phase). However, the chromosomes and other associated elements like MTOCs, are duplicated just once during the cell cycle. A central component of the cell cycle is its ability to coordinate the continuous and periodic duplications of different cellular elements, which evolved with the formation of the genome. The pre cellular environment contained functional and self replicating RNAs. All RNA concentrations depended on the concentrations of other RNAs that might be helping or hindering the gathering of resources. In this environment, growth was simply the continuous production of RNAs. These pre cellular structures would have had to contend with parasitic RNAs, issues of inheritance, and copy number control of specific RNAs. Partitioning "genomic" RNA from "functional" RNA helped solve these problems. The fusion of multiple RNAs into a genome gave a template from which functional RNAs were cleaved. Now, parasitic RNAs would have to incorporate themselves into the genome, a much greater barrier, in order to survive. Controlling the copy number of genomic RNA also allowed RNA concentration to be determined through synthesis rates and RNA half lives, instead of competition. However, in animals, whole families of CDKs have evolved. Cdk1 controls entry to mitosis and Cdk2, Cdk4, and Cdk6 regulate entry into S phase. Despite the evolution of the CDK family in animals, these proteins have related or redundant functions. For example, cdk2 cdk4 cdk6 triple knockout mice cells can still progress through the basic cell cycle. cdk1 knockouts are lethal, which suggests an ancestral CDK1 type kinase ultimately controlling the cell cycle. running counter to the opisthokont pattern of CDK1 type kinases as essential regulators controlling the cell cycle. Plants also have a unique group of B type CDKs, whose functions may range from development specific functions to major players in mitotic regulation.

[[File:G1 S checkpoint regulation across eukaryotes. jpg|thumb|Overviews of the G1/S transition control networks in plants, animals, and yeast. All three show striking network topology similarities, even though individual proteins in the network have very little sequence similarity. Entry into S phase in both yeast and animals is controlled by the levels of two opposing regulators. Additional regulation of the regulatory network for the G1/S checkpoint in yeast and animals includes the phosphorylation/de phosphorylation of CDK cyclin complexes. The sum of these regulatory networks creates a hysteretic and bistable scheme, despite the specific proteins being highly diverged. For yeast, Whi5 must be suppressed by Cln3 phosphorylation for SBF to be expressed, while in animals Rb must be suppressed by the Cdk4/6 cyclin D complex for E2F to be expressed. Both Rb and Whi5 inhibit transcript through the recruitment of histone deacetylase proteins to promoters. Both proteins additionally have multiple CDK phosphorylation sites through which they are inhibited. For example, plants also need to suppress Rb for E2F translation in the network. These conserved elements of the plant and animal cell cycles may be ancestral in eukaryotes. While yeast share a conserved network topology with plants and animals, the highly diverged nature of yeast regulators suggests possible rapid evolution along the yeast lineage.