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Histone
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== Synthesis == The first step of chromatin structure duplication is the synthesis of histone proteins: H1, H2A, H2B, H3, H4. These proteins are synthesized during S phase of the cell cycle. There are different mechanisms which contribute to the increase of histone synthesis. === Yeast === Yeast carry one or two copies of each histone gene, which are not clustered but rather scattered throughout chromosomes. Histone gene transcription is controlled by multiple gene regulatory proteins such as transcription factors which bind to histone promoter regions. In budding yeast, the candidate gene for activation of histone gene expression is SBF. SBF is a transcription factor that is activated in late G1 phase, when it dissociates from its repressor [[Whi5]]. This occurs when [[Whi5]] is phosphorylated by Cdc8 which is a G1/S Cdk.<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 = 887β98 | date = June 2004 | pmid = 15210110 | doi = 10.1016/j.cell.2004.05.025 | doi-access = free }}</ref> Suppression of histone gene expression outside of S phases is dependent on Hir proteins which form inactive chromatin structure at the locus of histone genes, causing transcriptional activators to be blocked.<ref>{{cite journal | vauthors = Xu H, Kim UJ, Schuster T, Grunstein M | title = Identification of a new set of cell cycle-regulatory genes that regulate S-phase transcription of histone genes in Saccharomyces cerevisiae | journal = Molecular and Cellular Biology | volume = 12 | issue = 11 | pages = 5249β59 | date = November 1992 | pmid = 1406694 | pmc = 360458 | doi = 10.1128/mcb.12.11.5249 }}</ref><ref>{{cite journal | vauthors = Dimova D, Nackerdien Z, Furgeson S, Eguchi S, Osley MA | title = A role for transcriptional repressors in targeting the yeast Swi/Snf complex | journal = Molecular Cell | volume = 4 | issue = 1 | pages = 75β83 | date = July 1999 | pmid = 10445029 | doi = 10.1016/S1097-2765(00)80189-6 | doi-access = free }}</ref> === Metazoan === In [[metazoan]]s the increase in the rate of histone synthesis is due to the increase in processing of pre-mRNA to its mature form as well as decrease in mRNA degradation; this results in an increase of active mRNA for translation of histone proteins. The mechanism for mRNA activation has been found to be the removal of a segment of the 3' end of the mRNA strand, and is dependent on association with stem-loop binding protein ([[SLBP]]).<ref>{{cite journal | vauthors = Dominski Z, Erkmann JA, Yang X, SΓ nchez R, Marzluff WF | title = A novel zinc finger protein is associated with U7 snRNP and interacts with the stem-loop binding protein in the histone pre-mRNP to stimulate 3'-end processing | journal = Genes & Development | volume = 16 | issue = 1 | pages = 58β71 | date = January 2002 | pmid = 11782445 | pmc = 155312 | doi = 10.1101/gad.932302 }}</ref> SLBP also stabilizes histone mRNAs during S phase by blocking degradation by the 3'hExo nuclease.<ref>{{cite journal | vauthors = Dominski Z, Yang XC, Kaygun H, Dadlez M, Marzluff WF | title = A 3' exonuclease that specifically interacts with the 3' end of histone mRNA | journal = Molecular Cell | volume = 12 | issue = 2 | pages = 295β305 | date = August 2003 | pmid = 14536070 | doi = 10.1016/S1097-2765(03)00278-8 | doi-access = free }}</ref> SLBP levels are controlled by cell-cycle proteins, causing SLBP to accumulate as cells enter S phase and degrade as cells leave S phase. SLBP are marked for degradation by phosphorylation at two threonine residues by cyclin dependent kinases, possibly cyclin A/ cdk2, at the end of S phase.<ref>{{cite journal | vauthors = Zheng L, Dominski Z, Yang XC, Elms P, Raska CS, Borchers CH, Marzluff WF | title = Phosphorylation of stem-loop binding protein (SLBP) on two threonines triggers degradation of SLBP, the sole cell cycle-regulated factor required for regulation of histone mRNA processing, at the end of S phase | journal = Molecular and Cellular Biology | volume = 23 | issue = 5 | pages = 1590β601 | date = March 2003 | pmid = 12588979 | pmc = 151715 | doi = 10.1128/MCB.23.5.1590-1601.2003 }}</ref> Metazoans also have multiple copies of histone genes clustered on chromosomes which are localized in structures called Cajal bodies as determined by genome-wide chromosome conformation capture analysis (4C-Seq).<ref>{{cite journal | vauthors = Wang Q, Sawyer IA, Sung MH, Sturgill D, Shevtsov SP, Pegoraro G, Hakim O, Baek S, Hager GL, Dundr M | title = Cajal bodies are linked to genome conformation | journal = Nature Communications | volume = 7 | pages = 10966 | date = March 2016 | pmid = 26997247 | pmc = 4802181 | doi = 10.1038/ncomms10966 | bibcode = 2016NatCo...710966W }}</ref> === Link between cell-cycle control and synthesis === Nuclear protein Ataxia-Telangiectasia (NPAT), also known as nuclear protein coactivator of histone transcription, is a transcription factor which activates histone gene transcription on chromosomes 1 and 6 of human cells. NPAT is also a substrate of cyclin E-Cdk2, which is required for the transition between G1 phase and S phase. NPAT activates histone gene expression only after it has been phosphorylated by the G1/S-Cdk cyclin E-Cdk2 in early S phase.<ref>{{cite journal | vauthors = Zhao J, Kennedy BK, Lawrence BD, Barbie DA, Matera AG, Fletcher JA, Harlow E | title = NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription | journal = Genes & Development | volume = 14 | issue = 18 | pages = 2283β97 | date = September 2000 | pmid = 10995386 | pmc = 316937 | doi = 10.1101/GAD.827700 }}</ref> This shows an important regulatory link between cell-cycle control and histone synthesis.
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