Cell cycle - Knowledge (XXG)

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with cyclin levels. The enzymatic activities of cyclin–Cdk complexes also tend to rise and fall in parallel with cyclin levels, although in some cases Cdk inhibitor proteins or phosphorylation introduce a delay between the formation and activation of cyclin–Cdk complexes. Formation of active G1/S–Cdk complexes commits the cell to a new division cycle at the Start checkpoint in late G1. G1/S–Cdks then activate the S–Cdk complexes that initiate DNA replication at the beginning of S phase. M–Cdk activation occurs after the completion of S phase, resulting in progression through the G2/M checkpoint and assembly of the mitotic spindle. APC activation then triggers sister-chromatid separation at the metaphase-to-anaphase transition. APC activity also causes the destruction of S and M cyclins and thus the inactivation of Cdks, which promotes the completion of mitosis and cytokinesis. APC activity is maintained in G1 until G1/S–Cdk activity rises again and commits the cell to the next cycle. This scheme serves only as a general guide and does not apply to all cell types.

1707: 1297:. 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. 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. 1285:. 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. 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 . 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, 1348:, and subsequently, its deactivation causes the cell to exit mitosis. 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. 1023: 83: 1558:. 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. Other work indicates that 2020: 86: 90: 89: 85: 84: 91: 607: 88: 1532:

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).

1362: 1656:/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 G 873: 6465: 504: 57: 1045: 1951:

Controlling the copy number of genomic RNA also allowed RNA concentration to be determined through synthesis rates and RNA half-lives, instead of competition. 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

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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 G

65: 1947:. 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. 5833: 1058: 1955:, 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. 87: 2072:

as a whole. Plants also share a number of conserved network features with opisthokonts, and many plant regulators have direct animal homologs. 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

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that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell

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Levels of the three major cyclin types oscillate during the cell cycle (top), providing the basis for oscillations in the cyclin–Cdk complexes that drive cell-cycle events (bottom). In general, Cdk levels are constant and in large excess over cyclin levels; thus, cyclin–Cdk complexes form in parallel

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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

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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.

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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

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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

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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

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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

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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

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binding affinity. Rb has been found to associate with hundreds of different proteins 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

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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

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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

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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.

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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

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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

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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

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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

1983:) controls the cell cycle. 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, 1272:

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

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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. However, these proteins share no sequence similarity.

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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.

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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

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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

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and cell membrane 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

842:). It is a relatively short period of the cell cycle. M phase is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These phases are sequentially known as: 2032:

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.

1889:. 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. 985:

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

1616:. 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. 234:

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.

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In single-celled organisms, a single cell-division cycle is how the organism reproduces to ensure its survival. In multicellular organisms such as plants and animals, a series of cell-division cycles is how the organism develops from a single-celled

1170:. 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. 1638:/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. 969:

into two cells containing roughly equal shares of these cellular components. Cytokinesis occurs differently in plant and animal cells. While the cell membrane forms a groove that gradually deepens to separate the cytoplasm in animal cells, a

1940:, 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. 1100:

among all eukaryotes, but in general, more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially

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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

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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.

816:. 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. 5837: 666:

is highly variable, even among different cells of the same species. In this phase, the cell increases its supply of proteins, increases the number of organelles (such as mitochondria, ribosomes), and grows in size. In

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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

1649:. 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. 1547:). 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 2023:

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

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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

1502:(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 161:

that includes mitosis and 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

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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.

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are double-negative feedback loops and positive feedback loops in both yeast and animals. Additional regulation of the regulatory network for the G1/S checkpoint in yeast and animals includes the

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Bilgin B, Sendur MA, Şener Dede D, Akıncı MB, Yalçın B (September 2017). "A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer".

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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.

1185:. 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 662:). 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 G 4886:

Ortega S, Prieto I, Odajima J, Martín A, Dubus P, Sotillo R, et al. (September 2003). "Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice".

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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

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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

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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.

1130:; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called 1706: 521:

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

166:, 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 1846:

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

4037:. Miami Nature Biotechnology Winter Symposium. Cell Cycle, Chromosomes and Cancer. Vol. 15. Miami Beach, FL: University of Miami School of Medicine. Archived from 1672:

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

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Experimental evidence also suggests that gene expression can oscillate with the period seen in dividing wild-type cells independently of the CDK machinery. Orlando

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of the parent cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle.

5941: 2966:"Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase" 3754:

Lee TI, Rinaldi NJ, Robert F, Odom DT, Bar-Joseph Z, Gerber GK, et al. (October 2002). "Transcriptional regulatory networks in Saccharomyces cerevisiae".

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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 (

3552:"The Forkhead transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle" 1509:

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.

6233: 6127: 4065:"Integrative analysis of genome-scale data by using pseudoinverse projection predicts novel correlation between DNA replication and RNA transcription" 4975:

Santamaría D, Barrière C, Cerqueira A, Hunt S, Tardy C, Newton K, et al. (August 2007). "Cdk1 is sufficient to drive the mammalian cell cycle".

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The cell cycle must duplicate all cellular constituents and equally partition them into two daughter cells. Many constituents, such as proteins and

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responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like

564:. 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 4028:

Alter O, Golub GH, Brown PO, Botstein D (February 2004). Deutscher MP, Black S, Boehmer PE, D'Urso G, Fletcher TM, Huijing F, et al. (eds.).

5554:"The E2F functional analogue SBF recruits the Rpd3(L) HDAC, via Whi5 and Stb1, and the FACT chromatin reorganizer, to yeast G1 cyclin promoters" 4794:

Satyanarayana A, Kaldis P (August 2009). "Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms".

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is formed to separate it in plant cells. The position of the cell plate is determined by the position of a preprophase band of microtubules and

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Novel Genome-Scale Correlation between DNA Replication and RNA Transcription During the Cell Cycle in Yeast is Predicted by Data-Driven Models

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There are several checkpoints to ensure that damaged or incomplete DNA is not passed on to daughter cells. Three main checkpoints exist: the G

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hyper-phosphorylated Rb in late G1 state. In early G1 cells, mono-phosphorylated Rb exists as 14 different isoforms, one of each has distinct

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computational methods and criteria used to identify them, each study indicates that a large portion of yeast genes are temporally regulated.

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Ubersax JA, Woodbury EL, Quang PN, Paraz M, Blethrow JD, Shah K, et al. (October 2003). "Targets of the cyclin-dependent kinase Cdk1".

6173: 1698:/M checkpoints. In addition to p53, checkpoint regulators are being heavily researched for their roles in cancer growth and proliferation. 998:, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of 271:(mitosis and cytokinesis). M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's nucleus divides, and 5322:

Ferrell JE (April 2002). "Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability".

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are converted to about 50 endogenous DNA double-strand breaks per cell per cell cycle. Although such double-strand breaks are usually

5934: 5910: 5513:"Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1" 3135: 2141: 2440: 2036:

Entry into S-phase in both yeast and animals is controlled by the levels of two opposing regulators. The networks regulating these

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Fluorescent proteins visualize the cell cycle progression. IFP2.0-hGem(1/110) fluorescence is shown in green and highlights the S/G

1261:) to pRb. The un-phosphorylated Rb tumour suppressor functions in inducing cell cycle exit and maintaining G0 arrest (senescence). 122:, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called 5842: 4029: 1620: 3345: 1281:

In general, the binding of pRb to E2F inhibits the E2F target gene expression of certain G1/S and S transition genes including

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Mahmoudi M, Azadmanesh K, Shokrgozar MA, Journeay WS, Laurent S (May 2011). "Effect of nanoparticles on the cell life cycle".

2655:"Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization" 545:

phase semi-permanently and are considered post-mitotic, e.g., some liver, kidney, and stomach cells. Many cells do not enter G

4296:"Lack of checkpoint control at the metaphase/anaphase transition: a mechanism of meiotic nondisjunction in mammalian females" 2298:

Wu RS, Bonner WM (December 1981). "Separation of basal histone synthesis from S-phase histone synthesis in dividing cells".

1022: 4124:"A tensor higher-order singular value decomposition for integrative analysis of DNA microarray data from different studies" 1937: 6431: 5864: 4653:"Phylogeny from function: evidence from the molecular fossil record that tRNA originated in replication, not translation" 1162:

cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for

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cells, but occurs in different ways in different species. For example, animal cells undergo an "open" mitosis, where the

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transcription does not occur and all needed proteins, such as the B-type cyclins, are translated from maternally loaded

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may alter the localization or activity of the transcription factors in order to tightly control timing of target genes.

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The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis, is called

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Pioneering work by Atsushi Miyawaki and coworkers developed the fluorescent ubiquitination-based cell cycle indicator (

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with high fidelity, errors in their repair are considered to contribute significantly to the rate of cancer in humans.

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that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (

6445: 6243: 1915:, a less accurate and more mutagenic process for repairing double strand breaks, is active throughout the cell cycle. 1751: 1499: 1439:(which, in turn, is triggered by DNA damage e.g. due to radiation). p27 is activated by Transforming Growth Factor β ( 560:

cells. Cellular senescence occurs in response to DNA damage and external stress and usually constitutes an arrest in G

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Zhao X, Harashima H, Dissmeyer N, Pusch S, Weimer AK, Bramsiepe J, et al. (2 August 2012). Palanivelu R (ed.).

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Baserga R (June 1965). "The Relationship of the Cell Cycle to Tumor Growth and Control of Cell Division: A Review".

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could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.

1214: 594:, followed by the cycle of mitosis and cytokinesis. The cell's nuclear DNA contents are duplicated during S phase. 1858:, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G 6082: 6077: 6072: 6067: 6062: 6057: 6052: 6047: 6042: 1979: 1763: 1739: 1321: 1250: 1241: 1237: 5115:"B1-type cyclin-dependent kinases are essential for the formation of stomatal complexes in Arabidopsis thaliana" 1815: 1232:

is the first cyclin produced in the cells that enter the cell cycle, in response to extracellular signals (e.g.

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rame) family, prevent the progression of the cell cycle. Because these genes are instrumental in prevention of

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phases and most resistant in late S phase. For cells with a longer cell cycle time and a significantly long G

1221:. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed. 6034: 1968: 1174: 1097: 1077: 999: 4929:

Aleem E, Kiyokawa H, Kaldis P (August 2005). "Cdc2-cyclin E complexes regulate the G1/S phase transition".

3007:"The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle" 2102: 2053: 1991:

knockouts are lethal, which suggests an ancestral CDK1-type kinase ultimately controlling the cell cycle.

1831: 1570: 1258: 1253:/6, forming the active cyclin D-CDK4/6 complex. Cyclin D-CDK4/6 complexes in turn mono-phosphorylates the 215: 2550:

Lilly MA, Duronio RJ (April 2005). "New insights into cell cycle control from the Drosophila endocycle".

2392:"Evidence for an essentially constant duration of DNA synthesis in renewing epithelia of the adult mouse" 6366: 6117: 5078:

Harashima H, Dissmeyer N, Schnittger A (July 2013). "Cell cycle control across the eukaryotic kingdom".

2636: 1608: 1603: 1182: 716: 708: 476: 446: 396: 167: 4511:"DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells" 4441:

Champeris Tsaniras S, Kanellakis N, Symeonidou IE, Nikolopoulou P, Lygerou Z, Taraviras S (June 2014).

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Schmidt M, Sebastian M (August 2018). "Palbociclib—The First of a New Class of Cell Cycle Inhibitors".

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Nigg EA (June 1995). "Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle".

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been characterized to be a therapeutic target for anti-tumor effectiveness. Three Cdk4/6 inhibitors –

5359:"Double-negative feedback between S-phase cyclin-CDK and CKI generates abruptness in the G1/S switch" 5278: 4984: 4664: 4609: 4248: 4190: 4135: 4076: 3981:"Global effects of DNA replication and DNA replication origin activity on eukaryotic gene expression" 3912: 3763: 3617: 2754: 2252: 2037: 1995: 1528: 1151: 921: 770: 39: 170:

after each of the key steps of the cycle that determine if the cell can progress to the next phase.

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and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for

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Simon I, Barnett J, Hannett N, Harbison CT, Rinaldi NJ, Volkert TL, et al. (September 2001).

6379: 6184: 5008: 4954: 4911: 4819: 4633: 4374: 4214: 3936: 3836: 3787: 3488: 3445: 3265:"Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein's C-Terminal Helix" 2618: 2575: 2323: 1081: 5859: 5784:

Krieger M, Scott MP, Matsudaira PT, Lodish HF, Darnell JE, Zipursky L, Kaiser C, Berk A (2004).

5166:"Requirement of B2-type cyclin-dependent kinases for meristem integrity in Arabidopsis thaliana" 4343:

Sakaue-Sawano A, Kurokawa H, Morimura T, Hanyu A, Hama H, Osawa H, et al. (February 2008).

3321: 3313: 2343:"Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin/cdk2 activity" 1194:

effects, possession of extra copies of certain genes is also deleterious to the daughter cells.

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for their discovery of these central molecules. Many of the genes encoding cyclins and CDKs are

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Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF (June 2014). Davis R (ed.).

4443:"Licensing of DNA replication, cancer, pluripotency and differentiation: an interlinked world?" 3420:

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must be suppressed by Cln3 phosphorylation for SBF to be expressed, while in animals

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