Cell cycle
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
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.[2]
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
Phases
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 phase (quiescence)
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
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.
G1 phase (First growth phase or Post mitotic gap phase)
The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis, is called G1 (G indicating gap). It is also called the growth phase. During this phase, the biosynthetic activities of the cell, which are considerably slowed down during M phase, resume at a high rate. The duration of G1 is highly variable, even among different cells of the same species.[4] In this phase, the cell increases its supply of proteins, increases the number of organelles (such as mitochondria, ribosomes), and grows in size. In G1 phase, a cell has three options.
- To continue cell cycle and enter S phase
- Stop cell cycle and enter G0 phase for undergoing differentiation.
- Become arrested in G1 phase hence it may enter G0 phase or re-enter cell cycle.
The deciding point is called check point (Restriction point). This check point is called the restriction point or START and is regulated by G1/S cyclins, which cause transition from G1 to S phase. Passage through the G1 check point commits the cell to division.
S phase (DNA replication)
The ensuing
G2 phase (growth)
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.
Mitotic phase (chromosome separation)
The relatively brief M phase consists of nuclear division (
Mitosis is the process by which a
Mitosis occurs exclusively in
Cytokinesis phase (separation of all cell components)
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
Regulation of eukaryotic cell cycle
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.
Role of cyclins and CDKs
Nobel Laureate Paul Nurse |
Nobel Laureate Tim Hunt |
Two key classes of regulatory molecules,
Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated
General mechanism of cyclin-CDK interaction
Upon receiving a pro-mitotic extracellular signal, G1
Active S cyclin-CDK complexes phosphorylate proteins that make up the
Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of
Specific action of cyclin-CDK complexes
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,[18] 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).[19]
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.[20]
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.[21][22][23] In early G1 cells, mono-phosphorylated Rb exits as 14 different isoforms, one of each has distinct E2F binding affinity.[23] Rb has been found to associate with hundreds of different proteins[24] and the idea that different mono-phosphorylated Rb isoforms have different protein partners was very appealing.[25] A recent report confirmed that mono-phosphorylation controls Rb's association with other proteins and generates functional distinct forms of Rb.[26] 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.[26]
In general, the binding of pRb to E2F inhibits the E2F target gene expression of certain G1/S and S transition genes including E-type cyclins. The partial phosphorylation of Rb de-represses the Rb-mediated suppression of E2F target gene expression, begins the expression of cyclin E. The molecular mechanism that causes the cell switched to cyclin E activation is currently not known, but as cyclin E levels rise, the active cyclin E-CDK2 complex is formed, bringing Rb to be inactivated by hyper-phosphorylation.[23] Hyperphosphorylated Rb is completely dissociated from E2F, enabling further expression of a wide range of E2F target genes are required for driving cells to proceed into S phase [1]. Recently, it has been identified that cyclin D-Cdk4/6 binds to a C-terminal alpha-helix region of Rb that is only distinguishable to cyclin D rather than other cyclins, cyclin E, A and B.[27] 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.[27] This cyclin-Cdk driven cell cycle transitional mechanism governs a cell committed to the cell cycle that allows cell proliferation. A cancerous cell growth often accompanies with deregulation of Cyclin D-Cdk 4/6 activity.
The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the E2F responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. Cyclin E thus produced binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S, which initiates the G2/M transition).[28] Cyclin B-cdk1 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, its deactivation causes the cell to exit mitosis.[15] A quantitative study of E2F transcriptional dynamics at the single-cell level by using engineered fluorescent reporter cells provided a quantitative framework for understanding the control logic of cell cycle entry, challenging the canonical textbook model. Genes that regulate the amplitude of E2F accumulation, such as Myc, determine the commitment in cell cycle and S phase entry. G1 cyclin-CDK activities are not the driver of cell cycle entry. Instead, they primarily tune the timing of E2F increase, thereby modulating the pace of cell cycle progression.[16]
Inhibitors
Endogenous
Two families of genes, the cip/kip (CDK interacting protein/Kinase inhibitory protein) family and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) family, prevent the progression of the cell cycle. Because these genes are instrumental in prevention of
The cip/kip family includes the genes
The INK4a/ARF family includes
Synthetic
Synthetic inhibitors of Cdc25 could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.[29]
Many human cancers possess the hyper-activated Cdk 4/6 activities.
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.
Transcriptional regulatory network
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.[14][34][35] 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.[36]
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.[37] 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.[34][38] 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).[35][39]
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
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
DNA replication and DNA replication origin activity
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.[43] This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression,[44][45][46] and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.
Checkpoints
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.[48] 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.[48]
There are several checkpoints to ensure that damaged or incomplete DNA is not passed on to daughter cells. Three main checkpoints exist: the G1/S checkpoint, the G2/M checkpoint and the metaphase (mitotic) checkpoint. Another checkpoint is the Go checkpoint, in which the cells are checked for maturity. If the cells fail to pass this checkpoint by not being ready yet, they will be discarded from dividing.
G1/S transition is a rate-limiting step in the cell cycle and is also known as restriction point.[15] This is where the cell checks whether it has enough raw materials to fully replicate its DNA (nucleotide bases, DNA synthase, chromatin, etc.). An unhealthy or malnourished cell will get stuck at this checkpoint.
The G2/M checkpoint is where the cell ensures that it has enough cytoplasm and phospholipids for two daughter cells. But sometimes more importantly, it checks to see if it is the right time to replicate. There are some situations where many cells need to all replicate simultaneously (for example, a growing embryo should have a symmetric cell distribution until it reaches the mid-blastula transition). This is done by controlling the G2/M checkpoint.
The metaphase checkpoint is a fairly minor checkpoint, in that once a cell is in metaphase, it has committed to undergoing mitosis. However that's not to say it isn't important. In this checkpoint, the cell checks to ensure that the spindle has formed and that all of the chromosomes are aligned at the spindle equator before anaphase begins.[49]
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.
Fluorescence imaging of the cell cycle
Pioneering work by Atsushi Miyawaki and coworkers developed the fluorescent ubiquitination-based cell cycle indicator (FUCCI), which enables
Role in tumor formation
A disregulation of the cell cycle components may lead to
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
The fastest cycling mammalian cells in culture, crypt cells in the intestinal epithelium, have a cycle time as short as 9 to 10 hours. Stem cells in resting mouse skin may have a cycle time of more than 200 hours. Most of this difference is due to the varying length of G1, the most variable phase of the cycle. M and S do not vary much.
In general, cells are most radiosensitive in late M and G2 phases and most resistant in late S phase. For cells with a longer cell cycle time and a significantly long G1 phase, there is a second peak of resistance late in G1. The pattern of resistance and sensitivity correlates with the level of sulfhydryl compounds in the cell. Sulfhydryls are natural substances that protect cells from radiation damage and tend to be at their highest levels in S and at their lowest near mitosis.
Homologous recombination (HR) is an accurate process for repairing DNA double-strand breaks. HR is nearly absent in G1 phase, is most active in S phase, and declines in G2/M.[54] Non-homologous end joining, a less accurate and more mutagenic process for repairing double strand breaks, is active throughout the cell cycle.
Cell cycle evolution
Evolution of the genome
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.[55] 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.[55][56]
Partitioning "genomic" RNA from "functional" RNA helped solve these problems.[57] 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.[55] Separating the duplication of genomic RNAs from the generation of functional RNAs allowed for much greater duplication fidelity of genomic RNAs without compromising the production of functional RNAs. Finally, the replacement of genomic RNA with DNA, which is a more stable molecule, allowed for larger genomes. The transition from self-catalysis enzyme synthesis to genome-directed enzyme synthesis was a critical step in cell evolution, and had lasting implications on the cell cycle, which must regulate functional synthesis and genomic duplication in very different ways.[55]
Cyclin-dependent kinase and cyclin evolution
Cell-cycle progression is controlled by the oscillating concentrations of different cyclins and the resulting molecular interactions from the various cyclin-dependent kinases (CDKs). In yeast, just one CDK (Cdc28 in S. cerevisiae and Cdc2 in S. pombe) controls the cell cycle.[58] However, in animals, whole families of CDKs have evolved.[59][60] 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.[61][62][63] For example, cdk2 cdk4 cdk6 triple knockout mice cells can still progress through the basic cell cycle.[64] cdk1 knockouts are lethal, which suggests an ancestral CDK1-type kinase ultimately controlling the cell cycle.[64]
Arabidopsis thaliana has a Cdk1 homolog called CDKA;1, however cdka;1 A. thaliana mutants are still viable,[65] running counter to the opisthokont pattern of CDK1-type kinases as essential regulators controlling the cell cycle.[66] Plants also have a unique group of B-type CDKs, whose functions may range from development-specific functions to major players in mitotic regulation.[67][68]
G1/S checkpoint evolution
The G1/S checkpoint is the point at which the cell commits to division through the cell cycle. Complex regulatory networks lead to the G1/S transition decision. Across opisthokonts, there are both highly diverged protein sequences as well as strikingly similar network topologies.[66][69]
Entry into S-phase in both yeast and animals is controlled by the levels of two opposing regulators.[66] The networks regulating these transcription factors are double-negative feedback loops and positive feedback loops in both yeast and animals.[66][69][70] 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.[71][72] For yeast, Whi5 must be suppressed by Cln3 phosphorylation for SBF to be expressed,[73] while in animals Rb must be suppressed by the Cdk4/6-cyclin D complex for E2F to be expressed.[74] Both Rb and Whi5 inhibit transcript through the recruitment of histone deacetylase proteins to promoters.[75][76] Both proteins additionally have multiple CDK phosphorylation sites through which they are inhibited.[77][74] However, these proteins share no sequence similarity.
Studies in A. thaliana extend our knowledge of the G1/S transition across eukaryotes as a whole. Plants also share a number of conserved network features with opisthokonts, and many plant regulators have direct animal homologs.[78] For example, plants also need to suppress Rb for E2F translation in the network.[79] 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.[66]
See also
- Cellular model
- Eukaryotic DNA replication
- Mitotic catastrophe
- Origin recognition complex
- Retinoblastoma protein
- Synchronous culture – synchronization of cell cultures
- Wee1
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Further reading
- Morgan DO (2007). The Cell Cycle: Principles of Control. London: Published by New Science Press in association with Oxford University Press. ISBN 978-0-87893-508-6.
- Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2008). "Chapter 17". Molecular Biology of the Cell (5th ed.). New York: Garland Science. ISBN 978-0-8153-4111-6.
- Krieger M, Scott MP, Matsudaira PT, Lodish HF, Darnell JE, Zipursky L, Kaiser C, Berk A (2004). Molecular cell biology. New York: W.H. Freeman and CO. ISBN 978-0-7167-4366-8.
- Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R (2004). "Chapter 7". Molecular biology of the gene (5th ed.). San Francisco: Pearson/Benjamin Cummings. ISBN 978-0-8053-4642-8.
External links
- This article incorporates NCBI. Archived from the originalon 8 December 2009.
- David Morgan's Seminar: Controlling the Cell Cycle
- The cell cycle & Cell death Archived 30 October 2018 at the Wayback Machine
- Transcriptional program of the cell cycle: high-resolution timing
- Cell cycle and metabolic cycle regulated transcription in yeast
- Cell Cycle Animation 1Lec.com
- Cell Cycle
- Fucci:Using GFP to visualize the cell-cycle
- Science Creative Quarterly's overview of the cell cycle
- KEGG – Human Cell Cycle Archived 3 November 2008 at the Wayback Machine