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====General mechanism of cyclin-CDK interaction==== Upon receiving a pro-mitotic extracellular signal, G<sub>1</sub> [[cyclin-CDK]] complexes become active to prepare the cell for S phase, promoting the expression of [[transcription factor]]s that in turn promote the expression of S cyclins and of enzymes required for [[DNA replication]]. The G<sub>1</sub> cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for [[ubiquitination]]. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the [[proteasome]]. Results from a 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.<ref name="Dong, P. 2014">{{cite journal | vauthors = Dong P, Maddali MV, Srimani JK, Thélot F, Nevins JR, Mathey-Prevot B, You L | title = Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control | journal = Nature Communications | volume = 5 | pages = 4750 | date = September 2014 | pmid = 25175461 | pmc = 4164785 | doi = 10.1038/ncomms5750 | bibcode = 2014NatCo...5.4750D }}</ref> Active S cyclin-CDK complexes phosphorylate proteins that make up the [[pre-replication complex]]es assembled during G<sub>1</sub> phase on DNA [[origin of replication|replication origins]]. 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 [[genome]] 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 [[gene copy number]] effects, possession of extra copies of certain genes is also deleterious to the daughter cells. Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G<sub>2</sub> 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 = 3407–3432 | date = May 2011 | pmid = 21401073 | doi = 10.1021/cr1003166 }}</ref>
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