Editing S phase (section)

== Histone synthesis ==
Since new DNA must be packaged into [[nucleosome]]s to function properly, synthesis of canonical (non-variant) [[histone]] proteins occurs alongside DNA replication. During early S-phase, the cyclin E-Cdk2 complex phosphorylates [[NPAT (gene)|NPAT]], a nuclear coactivator of histone transcription.<ref name=":0">{{cite journal | vauthors = DeRan M, Pulvino M, Greene E, Su C, Zhao J | title = Transcriptional activation of histone genes requires NPAT-dependent recruitment of TRRAP-Tip60 complex to histone promoters during the G1/S phase transition | journal = Molecular and Cellular Biology | volume = 28 | issue = 1 | pages = 435–47 | date = January 2008 | pmid = 17967892 | pmc = 2223310 | doi = 10.1128/MCB.00607-07 }}</ref> NPAT is activated by phosphorylation and recruits the Tip60 chromatin remodeling complex to the promoters of histone genes.<ref name=":0" /> Tip60 activity removes inhibitory chromatin structures and drives a three to ten-fold increase in transcription rate.<ref name=":5" /><ref name=":0" />

In addition to increasing transcription of histone genes, S-phase entry also regulates histone production at the RNA level. Instead of [[Polyadenylation|polyadenylated tails]], canonical histone transcripts possess a conserved 3` [[Stem-loop|stem loop]] motif that selective binds to Stem Loop Binding Protein ([[SLBP]]).<ref name=":1">{{cite journal | vauthors = Marzluff WF, Koreski KP | title = Birth and Death of Histone mRNAs | journal = Trends in Genetics | volume = 33 | issue = 10 | pages = 745–759 | date = October 2017 | pmid = 28867047 | pmc = 5645032 | doi = 10.1016/j.tig.2017.07.014 }}</ref> SLBP binding is required for efficient processing, export, and translation of histone mRNAs, allowing it to function as a highly sensitive biochemical "switch".<ref name=":1" /> During S-phase, accumulation of SLBP acts together with NPAT to drastically increase the efficiency of histone production.<ref name=":1" /> However, once S-phase ends, both SLBP and bound RNA are rapidly degraded.<ref>{{cite journal | vauthors = Whitfield ML, Zheng LX, Baldwin A, Ohta T, Hurt MM, Marzluff WF | title = Stem-loop binding protein, the protein that binds the 3' end of histone mRNA, is cell cycle regulated by both translational and posttranslational mechanisms | journal = Molecular and Cellular Biology | volume = 20 | issue = 12 | pages = 4188–98 | date = June 2000 | pmid = 10825184 | pmc = 85788 | doi = 10.1128/MCB.20.12.4188-4198.2000 }}</ref> This immediately halts histone production and prevents a toxic buildup of free histones.<ref>{{cite journal | vauthors = Ma Y, Kanakousaki K, Buttitta L | title = How the cell cycle impacts chromatin architecture and influences cell fate | language = en | journal = Frontiers in Genetics | volume = 6 | pages = 19 | date = 2015 | pmid = 25691891 | pmc = 4315090 | doi = 10.3389/fgene.2015.00019 | doi-access = free }}</ref>