Editing Cell cycle (section)

== 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 [[ribosome]]s, are produced continuously throughout the cell cycle (except during [[Mitosis|M-phase]]). However, the chromosomes and other associated elements like [[Microtubule organizing center|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 [[RNA]]s.<ref name=":2">{{cite journal | vauthors = Nasmyth K | title = Evolution of the cell cycle | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 349 | issue = 1329 | pages = 271–281 | date = September 1995 | pmid = 8577838 | doi = 10.1098/rstb.1995.0113 }}</ref> 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.<ref name=":2" /><ref>{{cite journal | vauthors = Cavalier-Smith T | title = The origin of eukaryotic and archaebacterial cells | journal = Annals of the New York Academy of Sciences | volume = 503 | issue = 1 | pages = 17–54 | date = July 1987 | pmid = 3113314 | doi = 10.1111/j.1749-6632.1987.tb40596.x | s2cid = 38405158 | bibcode = 1987NYASA.503...17C }}</ref> 

Partitioning "genomic" RNA from "functional" RNA helped solve these problems.<ref>{{cite journal | vauthors = Maizels N, Weiner AM | title = Phylogeny from function: evidence from the molecular fossil record that tRNA originated in replication, not translation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 15 | pages = 6729–6734 | date = July 1994 | pmid = 8041690 | pmc = 44276 | doi = 10.1073/pnas.91.15.6729 | doi-access = free | bibcode = 1994PNAS...91.6729M }}</ref> 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.<ref name=":2" /> 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.<ref name=":2" />

===Cyclin-dependent kinase and cyclin evolution===
Cell-cycle progression is controlled by the oscillating concentrations of different [[cyclin]]s and the resulting molecular interactions from the various [[cyclin-dependent kinase]]s (CDKs). In yeast, just one CDK (Cdc28 in ''[[Saccharomyces cerevisiae|S. cerevisiae]]'' and Cdc2 in ''[[Schizosaccharomyces pombe|S. pombe]]'') controls the cell cycle.<ref>{{cite journal | vauthors = Morgan DO | title = Cyclin-dependent kinases: engines, clocks, and microprocessors | journal = Annual Review of Cell and Developmental Biology | volume = 13 | issue = 1 | pages = 261–291 | date = November 1997 | pmid = 9442875 | doi = 10.1146/annurev.cellbio.13.1.261 }}</ref> However, in animals, whole families of CDKs have evolved.<ref>{{cite journal | vauthors = Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, Morgan DO, Tsai LH, Wolgemuth DJ | display-authors = 6 | title = Cyclin-dependent kinases: a family portrait | journal = Nature Cell Biology | volume = 11 | issue = 11 | pages = 1275–1276 | date = November 2009 | pmid = 19884882 | pmc = 2914104 | doi = 10.1038/ncb1109-1275 }}</ref><ref>{{cite journal | vauthors = Satyanarayana A, Kaldis P | title = Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms | journal = Oncogene | volume = 28 | issue = 33 | pages = 2925–2939 | date = August 2009 | pmid = 19561645 | doi = 10.1038/onc.2009.170 | s2cid = 3096776 }}</ref> 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.<ref>{{cite journal | vauthors = Barrière C, Santamaría D, Cerqueira A, Galán J, Martín A, Ortega S, Malumbres M, Dubus P, Barbacid M | display-authors = 6 | title = Mice thrive without Cdk4 and Cdk2 | journal = Molecular Oncology | volume = 1 | issue = 1 | pages = 72–83 | date = June 2007 | pmid = 19383288 | pmc = 5543859 | doi = 10.1016/j.molonc.2007.03.001 }}</ref><ref>{{cite journal | vauthors = Ortega S, Prieto I, Odajima J, Martín A, Dubus P, Sotillo R, Barbero JL, Malumbres M, Barbacid M | display-authors = 6 | title = Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice | journal = Nature Genetics | volume = 35 | issue = 1 | pages = 25–31 | date = September 2003 | pmid = 12923533 | doi = 10.1038/ng1232 | s2cid = 19522248 }}</ref><ref>{{cite journal | vauthors = Aleem E, Kiyokawa H, Kaldis P | title = Cdc2-cyclin E complexes regulate the G1/S phase transition | journal = Nature Cell Biology | volume = 7 | issue = 8 | pages = 831–836 | date = August 2005 | pmid = 16007079 | doi = 10.1038/ncb1284 | s2cid = 10842071 }}</ref> For example, ''cdk2 cdk4 cdk6'' triple knockout mice cells can still progress through the basic cell cycle.<ref name=":3">{{cite journal | vauthors = Santamaría D, Barrière C, Cerqueira A, Hunt S, Tardy C, Newton K, Cáceres JF, Dubus P, Malumbres M, Barbacid M | display-authors = 6 | title = Cdk1 is sufficient to drive the mammalian cell cycle | journal = Nature | volume = 448 | issue = 7155 | pages = 811–815 | date = August 2007 | pmid = 17700700 | doi = 10.1038/nature06046 | s2cid = 4412772 | bibcode = 2007Natur.448..811S }}</ref> ''cdk1'' knockouts are lethal, which suggests an ancestral CDK1-type kinase ultimately controlling the cell cycle.<ref name=":3" />

''[[Arabidopsis thaliana]]'' has a Cdk1 homolog called CDKA;1, however ''cdka;1'' ''A. thaliana'' mutants are still viable,<ref>{{cite journal | vauthors = Nowack MK, Harashima H, Dissmeyer N, Zhao X, Bouyer D, Weimer AK, De Winter F, Yang F, Schnittger A | display-authors = 6 | title = Genetic framework of cyclin-dependent kinase function in Arabidopsis | journal = Developmental Cell | volume = 22 | issue = 5 | pages = 1030–1040 | date = May 2012 | pmid = 22595674 | doi = 10.1016/j.devcel.2012.02.015 | doi-access = free }}</ref> running counter to the [[opisthokont]] pattern of CDK1-type kinases as essential regulators controlling the cell cycle.<ref name=":4">{{cite journal | vauthors = Harashima H, Dissmeyer N, Schnittger A | title = Cell cycle control across the eukaryotic kingdom | journal = Trends in Cell Biology | volume = 23 | issue = 7 | pages = 345–356 | date = July 2013 | pmid = 23566594 | doi = 10.1016/j.tcb.2013.03.002 }}</ref> Plants also have a unique group of B-type CDKs, whose functions may range from development-specific functions to major players in mitotic regulation.<ref>{{cite journal | vauthors = Boudolf V, Barrôco R, Engler J, Verkest A, Beeckman T, Naudts M, Inzé D, De Veylder L | display-authors = 6 | title = B1-type cyclin-dependent kinases are essential for the formation of stomatal complexes in Arabidopsis thaliana | journal = The Plant Cell | volume = 16 | issue = 4 | pages = 945–955 | date = April 2004 | pmid = 15031414 | doi = 10.1105/tpc.021774 | pmc = 412868 | doi-access = free | bibcode = 2004PlanC..16..945B }}</ref><ref>{{cite journal | vauthors = Andersen SU, Buechel S, Zhao Z, Ljung K, Novák O, Busch W, Schuster C, Lohmann JU | display-authors = 6 | title = Requirement of B2-type cyclin-dependent kinases for meristem integrity in Arabidopsis thaliana | journal = The Plant Cell | volume = 20 | issue = 1 | pages = 88–100 | date = January 2008 | pmid = 18223038 | pmc = 2254925 | doi = 10.1105/tpc.107.054676 | bibcode = 2008PlanC..20...88A }}</ref>

===G1/S checkpoint evolution===
[[File:G1-S checkpoint regulation across eukaryotes.jpg|thumb|upright=1.5|Overviews of the G1/S transition control networks in plants, animals, and yeast. All three show striking network topology similarities, even though individual proteins in the network have very little sequence similarity.<ref name=":4" />]]
The [[Restriction point|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.<ref name=":4" /><ref name=":5">{{cite journal | vauthors = Cross FR, Buchler NE, Skotheim JM | title = Evolution of networks and sequences in eukaryotic cell cycle control | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 366 | issue = 1584 | pages = 3532–3544 | date = December 2011 | pmid = 22084380 | pmc = 3203458 | doi = 10.1098/rstb.2011.0078 }}</ref> 

Entry into S-phase in both yeast and animals is controlled by the levels of two opposing regulators.<ref name=":4" /> The networks regulating these [[transcription factor]]s are double-negative feedback loops and positive feedback loops in both yeast and animals.<ref name=":4" /><ref name=":5" /><ref>{{cite journal | vauthors = Skotheim JM, Di Talia S, Siggia ED, Cross FR | title = Positive feedback of G1 cyclins ensures coherent cell cycle entry | journal = Nature | volume = 454 | issue = 7202 | pages = 291–296 | date = July 2008 | pmid = 18633409 | pmc = 2606905 | doi = 10.1038/nature07118 | bibcode = 2008Natur.454..291S }}</ref> 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 [[Hysteresis|hysteretic]] and bistable scheme, despite the specific proteins being highly diverged.<ref>{{cite journal | vauthors = Ferrell JE | title = Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability | journal = Current Opinion in Cell Biology | volume = 14 | issue = 2 | pages = 140–148 | date = April 2002 | pmid = 11891111 | doi = 10.1016/S0955-0674(02)00314-9 }}</ref><ref>{{cite journal | vauthors = Venta R, Valk E, Kõivomägi M, Loog M | title = Double-negative feedback between S-phase cyclin-CDK and CKI generates abruptness in the G1/S switch | journal = Frontiers in Physiology | volume = 3 | pages = 459 | date = 2012 | pmid = 23230424 | pmc = 3515773 | doi = 10.3389/fphys.2012.00459 | doi-access = free }}</ref> For yeast, [[Whi5]] must be suppressed by Cln3 phosphorylation for SBF to be expressed,<ref>{{cite journal | vauthors = Eser U, Falleur-Fettig M, Johnson A, Skotheim JM | title = Commitment to a cellular transition precedes genome-wide transcriptional change | journal = Molecular Cell | volume = 43 | issue = 4 | pages = 515–527 | date = August 2011 | pmid = 21855792 | pmc = 3160620 | doi = 10.1016/j.molcel.2011.06.024 }}</ref> while in animals [[Retinoblastoma protein|Rb]] must be suppressed by the Cdk4/6-cyclin D complex for [[E2F]] to be expressed.<ref name=":6">{{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 | veditors = Davis R }}</ref> Both Rb and Whi5 inhibit transcript through the recruitment of histone deacetylase proteins to promoters.<ref>{{cite journal | vauthors = Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC | title = Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1 | journal = Cell | volume = 98 | issue = 6 | pages = 859–869 | date = September 1999 | pmid = 10499802 | doi = 10.1016/s0092-8674(00)81519-6 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Takahata S, Yu Y, Stillman DJ | title = The E2F functional analogue SBF recruits the Rpd3(L) HDAC, via Whi5 and Stb1, and the FACT chromatin reorganizer, to yeast G1 cyclin promoters | journal = The EMBO Journal | volume = 28 | issue = 21 | pages = 3378–3389 | date = November 2009 | pmid = 19745812 | pmc = 2776103 | doi = 10.1038/emboj.2009.270 }}</ref> Both proteins additionally have multiple CDK phosphorylation sites through which they are inhibited.<ref>{{cite journal | vauthors = de Bruin RA, McDonald WH, Kalashnikova TI, Yates J, Wittenberg C | title = Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5 | journal = Cell | volume = 117 | issue = 7 | pages = 887–898 | date = June 2004 | pmid = 15210110 | doi = 10.1016/j.cell.2004.05.025 | doi-access = free }}</ref><ref name=":6" /> However, these proteins share no sequence similarity. 

Studies in ''A. thaliana'' extend our knowledge of the G1/S transition across [[eukaryote]]s as a whole. Plants also share a number of conserved network features with opisthokonts, and many plant regulators have direct animal homologs.<ref>{{cite journal | vauthors = Zhao X, Harashima H, Dissmeyer N, Pusch S, Weimer AK, Bramsiepe J, Bouyer D, Rademacher S, Nowack MK, Novak B, Sprunck S, Schnittger A | display-authors = 6 | title = A general G1/S-phase cell-cycle control module in the flowering plant Arabidopsis thaliana | journal = PLOS Genetics | volume = 8 | issue = 8 | pages = e1002847 | date = 2012-08-02 | pmid = 22879821 | pmc = 3410867 | doi = 10.1371/journal.pgen.1002847 | doi-access = free | veditors = Palanivelu R }}</ref> For example, plants also need to suppress Rb for E2F translation in the network.<ref>{{cite journal | vauthors = Weimer AK, Nowack MK, Bouyer D, Zhao X, Harashima H, Naseer S, De Winter F, Dissmeyer N, Geldner N, Schnittger A | display-authors = 6 | title = Retinoblastoma related1 regulates asymmetric cell divisions in Arabidopsis | journal = The Plant Cell | volume = 24 | issue = 10 | pages = 4083–4095 | date = October 2012 | pmid = 23104828 | pmc = 3517237 | doi = 10.1105/tpc.112.104620 | bibcode = 2012PlanC..24.4083W }}</ref> 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.<ref name=":4" />