Editing Cell cycle (section)

===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" />