Cell cycle: Difference between revisions

{{About|the eukaryotic cell cycle| the prokaryotic cell cycle|fission (biology)| the separation of chromosomes that occurs as part of the cell cycle|mitosis| the academic journal|Cell Cycle (journal){{!}}''Cell Cycle'' (journal)}}

The '''cell cycle''', or '''cell-division cycle''', is the sequential series of events that take place in a [[cell (biology)|cell]] that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA ([[DNA replication]]) and some of its [[organelle]]s, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called [[cell division]].

In [[eukaryotic cells]] with(having nucleia ([[eukaryotecell nucleus]]s,) i.e.,including [[animal]], [[plant]], [[fungal]], and [[protist]] cells), the cell cycle is divided into two main stages: [[interphase]], and the [[mitosis|mitotic]] (M) phase]] (includingthat includes [[mitosis]] and [[cytokinesis]]).<ref name="Alberts2019">{{cite book | vauthors = Alberts B, Hopkin K, Johnson A, Morgan D, Raff M, Roberts K, Walter P |title=Essential cell biology |date=2019 |publisher=W. W. Norton & Company |location=New York London |isbn=9780393680393 |pages=624–625 |edition=Fifth}}</ref> During interphase, the cell grows, accumulating nutrients needed for mitosis, and replicates its DNA and some of its organelles. During the mitoticM phase, the replicated [[Chromosome|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 checkpoint]]s 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 [[prokaryote]]s, i.e., [[bacteria]] and [[archaea]]), the [[fission (biology)|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.<ref name="Wang2009">{{cite journal | vauthors = Wang JD, Levin PA | title = Metabolism, cell growth and the bacterial cell cycle | journal = Nature Reviews. Microbiology | volume = 7 | issue = 11 | pages = 822–7822–827 | date = November 2009 | pmid = 19806155 | pmc = 2887316 | doi = 10.1038/nrmicro2202 }}</ref>

In single-celled organisms, a single cell-division cycle is how the organism replicatesreproduces itself.to ensure it's survival. 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 cell]]s, and some [[viscus|internal organs]] are [[Regeneration (biology)|regenerated]] and [[Healing|healed]] (with possible exception of [[nerve]]s; see [[Nerve injury|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|G₁ phase]], [[S phase]] (synthesis), [[G2 phase|G₂ phase]] (collectively known as [[interphase]]) and [[Mitosis|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]] 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 [[G0 phase|G₀ phase]] or the resting phase.

Interphase representrepresents 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.

The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis, is called [[G1 phase|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.<ref name="pmid4515625">{{cite journal | vauthors = Smith JA, Martin L | title = Do cells cycle? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 70 | issue = 4 | pages = 1263–71263–1267 | date = April 1973 | pmid = 4515625 | pmc = 433472 | doi = 10.1073/pnas.70.4.1263 | doi-access = free | bibcode = 1973PNAS...70.1263S | doi-access = free }}</ref> 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.

The ensuing [[S phase]] starts when [[DNA synthesis]] commences; when it is complete, all of the [[chromosome]]s have been replicated, i.e., each chromosome consists of two sister [[chromatid]]s. 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 (genetics)|transcription]] and [[Protein biosynthesis|protein synthesis]] are very low during this phase. An exception to this is [[histone]] production, most of which occurs during the S phase.<ref name="pmid7199388">{{cite journal | vauthors = Wu RS, Bonner WM | title = Separation of basal histone synthesis from S-phase histone synthesis in dividing cells | journal = Cell | volume = 27 | issue = 2 Pt 1 | pages = 321–30321–330 | date = December 1981 | pmid = 7199388 | doi = 10.1016/0092-8674(81)90415-3 | s2cid = 12215040 }}</ref><ref name="pmid12370293">{{cite journal | vauthors = Nelson DM, Ye X, Hall C, Santos H, Ma T, Kao GD, Yen TJ, Harper JW, Adams PD | display-authors = 6 | title = Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin/cdk2 activity | journal = Molecular and Cellular Biology | volume = 22 | issue = 21 | pages = 7459–727459–7472 | date = November 2002 | pmid = 12370293 | pmc = 135676 | doi = 10.1128/MCB.22.21.7459-7472.2002 }}</ref><ref name="pmid14018040">{{cite journal | vauthors = Cameron IL, Greulich RC | title = Evidence for an essentially constant duration of DNA synthesis in renewing epithelia of the adult mouse | journal = The Journal of Cell Biology | volume = 18 | pagesissue = 31–401 | datepages = July 196331–40 | issuedate = 1July 1963 | pmid = 14018040 | pmc = 2106275 | doi = 10.1083/jcb.18.1.31 }}</ref>

The relatively brief ''M phase'' consists of nuclear division ([[karyokinesis]]) and division of cytoplasm ([[cytokinesis]]). 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:

[[Image:Mitosis Stages.svg|center|1100px900px|A diagram of the mitotic phases]]

Mitosis occurs exclusively in [[eukaryote|eukaryotic]] cells, but occurs in different ways in different species. For example, animal cells undergo an "open" mitosis, where the [[nuclear envelope]] breaks down before the chromosomes separate, while [[fungi]] such as ''[[Aspergillus nidulans]]'' and ''[[Saccharomyces cerevisiae]]'' ([[yeast]]) undergo a "closed" mitosis, where chromosomes divide within an intact [[cell nucleus]].<ref>{{cite journal | vauthors = De Souza CP, Osmani SA | title = Mitosis, not just open or closed | journal = Eukaryotic Cell | volume = 6 | issue = 9 | pages = 1521–71521–1527 | date = September 2007 | pmid = 17660363 | pmc = 2043359 | doi = 10.1128/EC.00178-07 }}</ref>

Mitosis is immediately followed by [[cytokinesis]], which divides the nuclei, [[cytoplasm]], [[organelle]]s and [[cell membrane]] 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 [[cell plate]] 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 [[actin]] filaments. Mitosis and cytokinesis together define the [[cell division|division]] of the motherparent 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 [[fungus|fungi]] and [[slime mold]]s, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of [[Drosophila melanogaster|fruit fly]] embryonic development.<ref name=Lilly>{{cite journal | vauthors = Lilly MA, Duronio RJ | title = New insights into cell cycle control from the Drosophila endocycle | journal = Oncogene | volume = 24 | issue = 17 | pages = 2765–752765–2775 | date = April 2005 | pmid = 15838513 | doi = 10.1038/sj.onc.1208610 | s2cid = 25473573 | doi-access = free }}</ref> Errors in mitosis can result in cell death through [[apoptosis]] or cause [[mutation]]s that may lead to [[cancer]].

Two key classes of regulatory molecules, [[cyclin]]s and [[cyclin-dependent kinase]]s (CDKs), determine a cell's progress through the cell cycle.<ref name="pmid7575488">{{cite journal | vauthors = Nigg EA | title = Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle | journal = BioEssays | volume = 17 | issue = 6 | pages = 471–80471–480 | date = June 1995 | pmid = 7575488 | doi = 10.1002/bies.950170603 | s2cid = 44307473 }}</ref> [[Leland H. Hartwell]], [[R. Timothy Hunt]], and [[Paul M. Nurse]] won the 2001 [[Nobel Prize in Physiology or Medicine]] for their discovery of these central molecules.<ref>{{cite web| url=http://nobelprize.org/nobel_prizes/medicine/laureates/2001/press.html | publisher=Nobelprize.org | title=The Nobel Prize in Physiology or Medicine 2001 -– Press release}}</ref> Many of the genes encoding cyclins and CDKs are [[conservation (genetics)|conserved]] 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 ''[[Saccharomyces cerevisiae]]'';<ref name="pmid9843569">{{cite journal | vauthors = Spellman PT, Sherlock G, Zhang MQ, Iyer VR, Anders K, Eisen MB, Brown PO, Botstein D, Futcher B | display-authors = 6 | title = Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization | journal = Molecular Biology of the Cell | volume = 9 | issue = 12 | pages = 3273–973273–3297 | date = December 1998 | pmid = 9843569 | pmc = 25624 | doi = 10.1091/mbc.9.12.3273 }}</ref> genetic nomenclature in yeast dubs many of these genes ''cdc'' (for "cell division cycle") followed by an identifying number, e.g. ''[[cdc25]]'' or ''[[cdc20]]''.

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.<ref>{{cite journal | vauthors = Mahmoudi M, Azadmanesh K, Shokrgozar MA, Journeay WS, Laurent S | title = Effect of nanoparticles on the cell life cycle | journal = Chemical Reviews | volume = 111 | issue = 5 | pages = 3407–323407–3432 | date = May 2011 | pmid = 21401073 | doi = 10.1021/cr1003166 }}</ref>

[[Cyclin D]] is the first cyclin produced in the cells that enter the cell cycle, in response to extracellular signals (e.g. [[growth factor]]s). Cyclin D levels stay low in resting cells that are not proliferating. Additionally, [[Cyclin-dependent kinase 4|CDK4/6]] and [[Cyclin-dependent kinase 2|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,<ref>{{cite journal | vauthors = Goel S, DeCristo MJ, McAllister SS, Zhao JJ | title = CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest | journal = Trends in Cell Biology | volume = 28 | issue = 11 | pages = 911–925 | date = November 2018 | pmid = 30061045 | pmc = 6689321 | doi = 10.1016/j.tcb.2018.07.002 }}</ref> 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 [[Cyclin-dependent kinase 4|CDK4]]/6, forming the active cyclin D-CDK4/6 complex. Cyclin D-CDK4/6 complexes in turn mono-phosphorylates the [[retinoblastoma]] susceptibility protein ([[Retinoblastoma protein|Rb]]) to pRb. The un-phosphorylated Rb tumour suppressor functions in inducing cell cycle exit and maintaining G0 arrest (senescence).<ref>{{cite journal | vauthors = Burkhart DL, Sage J | title = Cellular mechanisms of tumour suppression by the retinoblastoma gene | journal = Nature Reviews. Cancer | volume = 8 | issue = 9 | pages = 671–82671–682 | date = September 2008 | pmid = 18650841 | doipmc = 10.1038/nrc23996996492 | pmcdoi = 699649210.1038/nrc2399 }}</ref>

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.<ref>{{cite journal | vauthors = Paternot S, Bockstaele L, Bisteau X, Kooken H, Coulonval K, Roger PP | title = Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase | journal = Cell Cycle | volume = 9 | issue = 4 | pages = 689–99689–699 | date = February 2010 | pmid = 20107323 | doi = 10.4161/cc.9.4.10611 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Henley SA, Dick FA | title = The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle | journal = Cell Division | volume = 7 | issue = 1 | pages = 10 | date = March 2012 | pmid = 22417103 | pmc = 3325851 | doi = 10.1186/1747-1028-7-10 | doi-access = free }}</ref><ref name=":0">{{cite journal | vauthors = Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF | title = Cyclin D activates the Rb tumor suppressor by mono-phosphorylation | journal = eLife | volume = 3 | pages = e02872 | date = June 2014 | pmid = 24876129 | pmc = 4076869 | doi = 10.7554/eLife.02872 | doi-access = free }}</ref> In early G1 cells, mono-phosphorylated Rb exits as 14 different isoforms, one of each has distinct [[E2F]] binding affinity.<ref name=":0" /> Rb has been found to associate with hundreds of different proteins<ref>{{cite book | vauthors = Morris EJ, Dyson NJ | title = Retinoblastoma protein partners | volume = 82 | pages = [https://archive.org/details/advancesincancer0000unse_w5o8/page/1 1–54] | date = 2001-01-01 | pmid = 11447760 | doi = 10.1016/s0065-230x(01)82001-7 | publisher = Academic Press | isbn = 9780120066827 | series = Advances in Cancer Research | url = https://archive.org/details/advancesincancer0000unse_w5o8/page/1 }}</ref> and the idea that different mono-phosphorylated Rb isoforms have different protein partners was very appealing.<ref name="pmid27401552">{{cite journal | vauthors = Dyson NJ | title = RB1: a prototype tumor suppressor and an enigma | journal = Genes & Development | volume = 30 | issue = 13 | pages = 1492–5021492–1502 | date = July 2016 | pmid = 27401552 | pmc = 4949322 | doi = 10.1101/gad.282145.116 }}</ref> A recent report confirmed that mono-phosphorylation controls Rb's association with other proteins and generates functional distinct forms of Rb.<ref name="Sanidas">{{cite journal | vauthors = Sanidas I, Morris R, Fella KA, Rumde PH, Boukhali M, Tai EC, Ting DT, Lawrence MS, Haas W, Dyson NJ | display-authors = 6 | title = A Code of Mono-phosphorylation Modulates the Function of RB | language = en | journal = Molecular Cell | volume = 73 | issue = 5 | pages = 985–1000.e6 | date = March 2019 | pmid = 30711375 | pmc = 6424368 | doi = 10.1016/j.molcel.2019.01.004 }}</ref> 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 RBRb have distinct transcriptional outputs that are extended beyond E2F regulation.<ref name="Sanidas" />

In general, the binding of pRb to E2F inhibits the E2F target gene expression of certain G1/S and S transition genes including [[Cyclin E|E-type cyclins]]. The partial phosphorylation of RBRb 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.<ref name=":0" /> 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]], [[Cyclin A|A]] and [[Cyclin B|B]].<ref name=":1">{{cite journal | vauthors = Topacio BR, Zatulovskiy E, Cristea S, Xie S, Tambo CS, Rubin SM, Sage J, Kõivomägi M, Skotheim JM | display-authors = 6 | title = Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein's C-Terminal Helix | language = en | journal = Molecular Cell | volume = 74 | issue = 4 | pages = 758–770.e4 | date = May 2019 | pmid = 30982746 | pmc = 6800134 | doi = 10.1016/j.molcel.2019.03.020 }}</ref> 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.<ref name=":1" /> 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.

Synthetic inhibitors of [[Cdc25]] could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.<ref name="ref 1">{{cite web |url=http://pharmaxchange.info/presentations/cdc25.html# |title=Presentation on CDC25 PHOSPHATASES: A Potential Target for Novel Anticancer Agents |access-date=11 March 2010 |archive-url=https://web.archive.org/web/20160303231929/http://pharmaxchange.info/presentations/cdc25.html# |archive-date=3 March 2016 |url-status=dead}}</ref>

Many human cancers possess the hyper-activated Cdk 4/6 activities.<ref>{{cite journal | vauthors = Sherr CJ, Beach D, Shapiro GI | title = Targeting CDK4 and CDK6: From Discovery to Therapy | journal = Cancer Discovery | volume = 6 | issue = 4 | pages = 353–67353–367 | date = April 2016 | pmid = 26658964 | pmc = 4821753 | doi = 10.1158/2159-8290.cd-15-0894 }}</ref> 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 breast cancer|metastatic]], [[Hormone receptor positive breast tumor|hormone-receptor-positive]] (HR-positive, HR+), [[HER2 negative breast cancer|HER2-negative]] (HER2-) breast cancer.<ref>{{cite journal | vauthors = O'Leary B, Finn RS, Turner NC | title = Treating cancer with selective CDK4/6 inhibitors | journal = Nature Reviews. Clinical Oncology | volume = 13 | issue = 7 | pages = 417–30417–430 | date = July 2016 | pmid = 27030077 | doi = 10.1038/nrclinonc.2016.26 | s2cid = 23646632 }}</ref><ref name="Bilgin_2017">{{cite journal | vauthors = Bilgin B, Sendur MA, Şener Dede D, Akıncı MB, Yalçın B | title = A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer | journal = Current Medical Research and Opinion | volume = 33 | issue = 9 | pages = 1559–1569 | date = September 2017 | pmid = 28657360 | doi = 10.1080/03007995.2017.1348344 | s2cid = 205542255 }}</ref> 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.<ref name="Schmidt_2018">{{cite journalbook | vauthors = Schmidt M, Sebastian M | title = Palbociclib-TheSmall Molecules in Oncology | chapter = Palbociclib—The First of a New Class of Cell Cycle Inhibitors | journalseries = Recent Results in Cancer Research. Fortschritte der Krebsforschung. Progres dans les Recherches Sur le Cancer | volume = 211 | pages = 153–175 | date = August 2018 | pmid = 30069766 | doi = 10.1007/978-3-319-91442-8_11 | isbn = 978-3-319-91441-1 | series = Recent Results in Cancer Research }}</ref>

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.<ref name="pmid9843569" /><ref name="pramilaetal2006">{{cite journal | vauthors = Pramila T, Wu W, Miles S, Noble WS, Breeden LL | title = The Forkhead transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle | journal = Genes & Development | volume = 20 | issue = 16 | pages = 2266–782266–2278 | date = August 2006 | pmid = 16912276 | pmc = 1553209 | doi = 10.1101/gad.1450606 }}</ref><ref name="orlandoeta1nature2008">{{cite journal | vauthors = Orlando DA, Lin CY, Bernard A, Wang JY, Socolar JE, Iversen ES, Hartemink AJ, Haase SB | display-authors = 6 | title = Global control of cell-cycle transcription by coupled CDK and network oscillators | journal = Nature | volume = 453 | issue = 7197 | pages = 944–7944–947 | date = June 2008 | pmid = 18463633 | pmc = 2736871 | doi = 10.1038/nature06955 | bibcode = 2008Natur.453..944O }}</ref> 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.<ref name="deLichtenberg2005">{{cite journal | vauthors = de Lichtenberg U, Jensen LJ, Fausbøll A, Jensen TS, Bork P, Brunak S | title = Comparison of computational methods for the identification of cell cycle-regulated genes | journal = Bioinformatics | volume = 21 | issue = 7 | pages = 1164–711164–1171 | date = April 2005 | pmid = 15513999 | doi = 10.1093/bioinformatics/bti093 | doi-access = free }}</ref>

Many periodically expressed genes are driven by [[transcription factor]]s 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.<ref name="whiteetal2009">{{cite journal | vauthors = White MA, Riles L, Cohen BA | title = A systematic screen for transcriptional regulators of the yeast cell cycle | journal = Genetics | volume = 181 | issue = 2 | pages = 435–46435–446 | date = February 2009 | pmid = 19033152 | pmc = 2644938 | doi = 10.1534/genetics.108.098145 }}</ref> 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.<ref name="pramilaetal2006" /><ref name="leeetal2002">{{cite journal | vauthors = Lee TI, Rinaldi NJ, Robert F, Odom DT, Bar-Joseph Z, Gerber GK, Hannett NM, Harbison CT, Thompson CM, Simon I, Zeitlinger J, Jennings EG, Murray HL, Gordon DB, Ren B, Wyrick JJ, Tagne JB, Volkert TL, Fraenkel E, Gifford DK, Young RA | display-authors = 6 | title = Transcriptional regulatory networks in Saccharomyces cerevisiae | journal = Science | volume = 298 | issue = 5594 | pages = 799–804 | date = October 2002 | pmid = 12399584 | doi = 10.1126/science.1075090 | s2cid = 4841222 | bibcode = 2002Sci...298..799L | s2cid = 4841222 }}</ref> 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).<ref name="orlandoeta1nature2008" /><ref name="simonetal2001">{{cite journal | vauthors = Simon I, Barnett J, Hannett N, Harbison CT, Rinaldi NJ, Volkert TL, Wyrick JJ, Zeitlinger J, Gifford DK, Jaakkola TS, Young RA | display-authors = 6 | title = Serial regulation of transcriptional regulators in the yeast cell cycle | journal = Cell | volume = 106 | issue = 6 | pages = 697–708 | date = September 2001 | pmid = 11572776 | doi = 10.1016/S0092-8674(01)00494-9 | s2cid = 9308235 | doi-access = free }}</ref>

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 [[microarray]]s 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 phase|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.<ref name="orlandoeta1nature2008" /> Other work indicates that [[phosphorylation]], a post-translational modification, of cell cycle transcription factors by [[Cdk1]] may alter the localization or activity of the transcription factors in order to tightly control timing of target genes.<ref name="whiteetal2009" /><ref name="sidorova1995">{{cite journal | vauthors = Sidorova JM, Mikesell GE, Breeden LL | title = Cell cycle-regulated phosphorylation of Swi6 controls its nuclear localization | journal = Molecular Biology of the Cell | volume = 6 | issue = 12 | pages = 1641–581641–1658 | date = December 1995 | pmid = 8590795 | pmc = 301322 | doi = 10.1091/mbc.6.12.1641 }}</ref><ref name="ubersaxetal2003">{{cite journal | vauthors = Ubersax JA, Woodbury EL, Quang PN, Paraz M, Blethrow JD, Shah K, Shokat KM, Morgan DO | display-authors = 6 | title = Targets of the cyclin-dependent kinase Cdk1 | journal = Nature | volume = 425 | issue = 6960 | pages = 859–64859–864 | date = October 2003 | pmid = 14574415 | doi = 10.1038/nature02062 | s2cid = 4391711 | bibcode = 2003Natur.425..859U | s2cid = 4391711 }}</ref>

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.<ref>{{cite journal | vauthors = Omberg L, Meyerson JR, Kobayashi K, Drury LS, Diffley JF, Alter O | title = Global effects of DNA replication and DNA replication origin activity on eukaryotic gene expression | journal = Molecular Systems Biology | volume = 5 | pages = 312 | date = October 2009 | pmid = 19888207 | pmc = 2779084 | doi = 10.1038/msb.2009.70 }}</ref> This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression,<ref>{{cite conference | vauthors = Alter O, Golub GH, Brown PO, Botstein D | title = Novel Genome-Scale Correlation between DNA Replication and RNA Transcription During the Cell Cycle in Yeast is Predicted by Data-Driven Models | veditors = Deutscher MP, Black S, Boehmer PE, D'Urso G, Fletcher TM, Huijing F, Marshall A, Pulverer B, Renault B, Rosenblatt JD, Slingerland JM, Whelan WJ | display-editors = 6 | conference = Miami Nature Biotechnology Winter Symposium | series = Cell Cycle, Chromosomes and Cancer | location = Miami Beach, FL | publisher = University of Miami School of Medicine | volume = 15 | date = February 2004 | url = http://www.med.miami.edu/mnbws/documents/Alter-.pdf | access-date = 7 February 2014 | archive-date = 9 September 2014 | archive-url = https://web.archive.org/web/20140909235805/http://www.med.miami.edu/mnbws/documents/Alter-.pdf | url-status = dead }}</ref><ref>{{cite journal | vauthors = Alter O, Golub GH | title = Integrative analysis of genome-scale data by using pseudoinverse projection predicts novel correlation between DNA replication and RNA transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 47 | pages = 16577–8216577–16582 | date = November 2004 | pmid = 15545604 | pmc = 534520 | doi = 10.1073/pnas.0406767101 | bibcodedoi-access = 2004PNAS..10116577Afree | doi-accessbibcode = free2004PNAS..10116577A }}</ref><ref>{{cite journal | vauthors = Omberg L, Golub GH, Alter O | title = A tensor higher-order singular value decomposition for integrative analysis of DNA microarray data from different studies | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 47 | pages = 18371–618371–18376 | date = November 2007 | pmid = 18003902 | pmc = 2147680 | doi = 10.1073/pnas.0709146104 | bibcodedoi-access = 2007PNAS..10418371Ofree | doi-accessbibcode = free2007PNAS..10418371O }}</ref> and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.

[[Cell cycle checkpoint]]s are used by the cell to monitor and regulate the progress of the cell cycle.<ref>{{cite journal | vauthors = Elledge SJ | title = Cell cycle checkpoints: preventing an identity crisis | journal = Science | volume = 274 | issue = 5293 | pages = 1664–721664–1672 | date = December 1996 | pmid = 8939848 | doi = 10.1126/science.274.5293.1664 | s2cid = 39235426 | bibcode = 1996Sci...274.1664E | s2cid = 39235426 }}</ref> 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 [[DNA damage (naturally occurring)|single-strand DNA damages]] are converted to about 50 endogenous DNA double-strand breaks per cell per cell cycle.<ref name = Vilenchik2003>{{cite journal | vauthors = Vilenchik MM, Knudson AG | title = Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 22 | pages = 12871–612871–12876 | date = October 2003 | pmid = 14566050 | pmc = 240711 | doi = 10.1073/pnas.2135498100 | bibcodedoi-access = 2003PNAS..10012871Vfree | doi-accessbibcode = free2003PNAS..10012871V }}</ref> Although such double-strand breaks are usually [[DNA repair|repaired]] with high fidelity, errors in their repair are considered to contribute significantly to the rate of cancer in humans.<ref name = Vilenchik2003/>

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.<ref>{{cite journal | vauthors = LeMaire-Adkins R, Radke K, Hunt PA | title = Lack of checkpoint control at the metaphase/anaphase transition: a mechanism of meiotic nondisjunction in mammalian females | journal = The Journal of Cell Biology | volume = 139 | issue = 7 | pages = 1611–91611–1619 | date = December 1997 | pmid = 9412457 | pmc = 2132649 | doi = 10.1083/jcb.139.7.1611 }}</ref>

Pioneering work by Atsushi Miyawaki and coworkers developed the fluorescent ubiquitination-based cell cycle indicator ([http://www.conncoll.edu/ccacad/zimmer/GFP-ww/cooluses19.html 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|nuclear localization signal]] and [[ubiquitination]] sites for [[Protein degradation|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.<ref>{{cite journal | vauthors = Sakaue-Sawano A, Kurokawa H, Morimura T, Hanyu A, Hama H, Osawa H, Kashiwagi S, Fukami K, Miyata T, Miyoshi H, Imamura T, Ogawa M, Masai H, Miyawaki A | display-authors = 6 | title = Visualizing spatiotemporal dynamics of multicellular cell-cycle progression | journal = Cell | volume = 132 | issue = 3 | pages = 487–98487–498 | date = February 2008 | pmid = 18267078 | doi = 10.1016/j.cell.2007.12.033 | s2cid = 15704902 | doi-access = free }}</ref> A far-red and near-infrared FUCCI was developed using a [[cyanobacteria]]-derived [[fluorescent protein]] ([[smURFP]]) and a [[Phytochrome|bacteriophytochrome]]-derived [[fluorescent protein]] ([http://www.nature.com/nmeth/journal/vaop/ncurrent/fig_tab/nmeth.3935_SV2.html movie found at this link]).<ref>{{cite journal | vauthors = Rodriguez EA, Tran GN, Gross LA, Crisp JL, Shu X, Lin JY, Tsien RY | title = A far-red fluorescent protein evolved from a cyanobacterial phycobiliprotein | journal = Nature Methods | volume = 13 | issue = 9 | pages = 763–9763–769 | date = September 2016 | pmid = 27479328 | pmc = 5007177 | doi = 10.1038/nmeth.3935 }}</ref>

A disregulation of the cell cycle components may lead to [[tumor]] formation.<ref>{{cite journal | vauthors = Champeris Tsaniras S, Kanellakis N, Symeonidou IE, Nikolopoulou P, Lygerou Z, Taraviras S | title = Licensing of DNA replication, cancer, pluripotency and differentiation: an interlinked world? | journal = Seminars in Cell & Developmental Biology | volume = 30 | pages = 174–80174–180 | date = June 2014 | pmid = 24641889 | doi = 10.1016/j.semcdb.2014.03.013 | doi-access = free }}</ref> As mentioned above, when some genes like the cell cycle inhibitors, [[Retinoblastoma protein|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.<ref name="Baserga_1965">{{cite journal | vauthors = Baserga R | title = The Relationship of the Cell Cycle to Tumor Growth and Control of Cell Division: A Review | journal = Cancer Research | volume = 25 | issue = 5 | pages = 581–95581–595 | date = June 1965 | pmid = 14347544 | doi = | url = https://aacrjournals.org/cancerres/article/25/5_Part_1/581/475748/The-Relationship-of-the-Cell-Cycle-to-Tumor-Growth }}</ref> Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same.

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.

* [https://www.kasem.info/histology-lectures/first-year-histology-lectures/the-cell-cycle The cell cycle & Cell death] {{Webarchive|url=https://web.archive.org/web/20181030131240/https://www.kasem.info/histology-lectures/first-year-histology-lectures/the-cell-cycle |date=30 October 2018 }}