CENPA

CENPA is a protein which epigenetically defines the position of the centromere on each chromosome,{{cite journal | vauthors = Fachinetti D, Folco HD, Nechemia-Arbely Y, Valente LP, Nguyen K, Wong AJ, Zhu Q, Holland AJ, Desai A, Jansen LE, Cleveland DW | title = A two-step mechanism for epigenetic specification of centromere identity and function | journal = Nature Cell Biology | volume = 15 | issue = 9 | pages = 1056–1066 | date = September 2013 | pmid = 23873148 | pmc = 4418506 | doi = 10.1038/ncb2805 }} determining the position of kinetochore assembly and the final site of sister chromatid cohesion during mitosis. This proteins is frequently accompanied by "centrochromatin"-associated changes to canonical histones and is constitutively present in centromeres.{{cite journal | vauthors = Altemose N, Logsdon GA, Bzikadze AV, Sidhwani P, Langley SA, Caldas GV, Hoyt SJ, Uralsky L, Ryabov FD, Shew CJ, Sauria ME, Borchers M, Gershman A, Mikheenko A, Shepelev VA, Dvorkina T, Kunyavskaya O, Vollger MR, Rhie A, McCartney AM, Asri M, Lorig-Roach R, Shafin K, Lucas JK, Aganezov S, Olson D, de Lima LG, Potapova T, Hartley GA, Haukness M, Kerpedjiev P, Gusev F, Tigyi K, Brooks S, Young A, Nurk S, Koren S, Salama SR, Paten B, Rogaev EI, Streets A, Karpen GH, Dernburg AF, Sullivan BA, Straight AF, Wheeler TJ, Gerton JL, Eichler EE, Phillippy AM, Timp W, Dennis MY, O'Neill RJ, Zook JM, Schatz MC, Pevzner PA, Diekhans M, Langley CH, Alexandrov IA, Miga KH | title = Complete genomic and epigenetic maps of human centromeres | journal = Science | volume = 376 | issue = 6588 | pages = eabl4178 | date = April 2022 | pmid = 35357911 | pmc = 9233505 | doi = 10.1126/science.abl4178 }} The CENPA protein is a histone H3 variant which replaces one or both canonical H3 histones in a subset of nucleosomes within centromeric chromatin.{{cite journal | vauthors = Blower MD, Sullivan BA, Karpen GH | title = Conserved organization of centromeric chromatin in flies and humans | journal = Developmental Cell | volume = 2 | issue = 3 | pages = 319–330 | date = March 2002 | pmid = 11879637 | pmc = 3192492 | doi = 10.1016/s1534-5807(02)00135-1 }}{{cite journal | vauthors = Nechemia-Arbely Y, Fachinetti D, Miga KH, Sekulic N, Soni GV, Kim DH, Wong AK, Lee AY, Nguyen K, Dekker C, Ren B, Black BE, Cleveland DW | title = Human centromeric CENP-A chromatin is a homotypic, octameric nucleosome at all cell cycle points | journal = The Journal of Cell Biology | volume = 216 | issue = 3 | pages = 607–621 | date = March 2017 | pmid = 28235947 | pmc = 5350519 | doi = 10.1083/jcb.201608083 }} CENPA has the greatest sequence divergence of the histone H3 variants, with just 48% similarity to canonical histone H3, and has a highly diverged N-terminal tail that lacks many well characterised histone modification sites including H3K4, H3K9 and H3K27.{{cite journal | vauthors = Srivastava S, Foltz DR | title = Posttranslational modifications of CENP-A: marks of distinction | journal = Chromosoma | volume = 127 | issue = 3 | pages = 279–290 | date = September 2018 | pmid = 29569072 | pmc = 6082721 | doi = 10.1007/s00412-018-0665-x }}

Unusually for a histone, CENPA nucleosomes are not loaded together with DNA replication and are loaded at different cell cycle stages in different organisms: G1 phase in human,{{cite journal | vauthors = Jansen LE, Black BE, Foltz DR, Cleveland DW | title = Propagation of centromeric chromatin requires exit from mitosis | journal = The Journal of Cell Biology | volume = 176 | issue = 6 | pages = 795–805 | date = March 2007 | pmid = 17339380 | pmc = 2064054 | doi = 10.1083/jcb.200701066 }} M phase in drosophila,{{cite journal | vauthors = Schuh M, Lehner CF, Heidmann S | title = Incorporation of Drosophila CID/CENP-A and CENP-C into centromeres during early embryonic anaphase | journal = Current Biology | volume = 17 | issue = 3 | pages = 237–243 | date = February 2007 | pmid = 17222555 | doi = 10.1016/j.cub.2006.11.051 | bibcode = 2007CBio...17..237S | hdl-access = free | s2cid = 17907028 | hdl = 11858/00-001M-0000-002A-23E4-7 }} G2 in S. pombe.{{cite journal | vauthors = Shukla M, Tong P, White SA, Singh PP, Reid AM, Catania S, Pidoux AL, Allshire RC | title = Centromere DNA Destabilizes H3 Nucleosomes to Promote CENP-A Deposition during the Cell Cycle | journal = Current Biology | volume = 28 | issue = 24 | pages = 3924–3936.e4 | date = December 2018 | pmid = 30503616 | pmc = 6303189 | doi = 10.1016/j.cub.2018.10.049 | bibcode = 2018CBio...28E3924S }} To orchestrate this specialised loading there are CENPA-specific histone chaperones: HJURP in human, CAL1 in drosophila and Scm3 in S. pombe.{{cite journal | vauthors = Gurard-Levin ZA, Quivy JP, Almouzni G | title = Histone chaperones: assisting histone traffic and nucleosome dynamics | journal = Annual Review of Biochemistry | volume = 83 | pages = 487–517 | date = 2014 | pmid = 24905786 | doi = 10.1146/annurev-biochem-060713-035536 }} In most eukaryotes CENPA is loaded into large domains of highly repetitive satellite DNA.{{cite journal | vauthors = Plohl M, Meštrović N, Mravinac B | title = Centromere identity from the DNA point of view | journal = Chromosoma | volume = 123 | issue = 4 | pages = 313–325 | date = August 2014 | pmid = 24763964 | pmc = 4107277 | doi = 10.1007/s00412-014-0462-0 }} The position of CENPA within satellite DNA are heritable at the protein level through a purely epigenetic mechanism.{{cite journal | vauthors = Aldrup-MacDonald ME, Kuo ME, Sullivan LL, Chew K, Sullivan BA | title = Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles | journal = Genome Research | volume = 26 | issue = 10 | pages = 1301–1311 | date = October 2016 | pmid = 27510565 | pmc = 5052062 | doi = 10.1101/gr.206706.116 }} This means that the position of CENPA protein binding to the genome is copied upon cell division to the two daughter cells independent of the underlying DNA sequence. Under circumstances in which CENPA is lost from a chromosome a fail-safe mechanism has been described in human cells in which CENPB recruits CENPA via a satellite DNA binding domain to repopulate the centromere with CENPA nucleosomes.{{cite journal | vauthors = van den Berg SJ, Jansen LE | title = Centromeres: genetic input to calibrate an epigenetic feedback loop | journal = The EMBO Journal | volume = 39 | issue = 20 | pages = e106638 | date = October 2020 | pmid = 32959893 | pmc = 7560195 | doi = 10.15252/embj.2020106638 }}

CENPA interacts directly with the inner kinetochore through proteins including CENPC and CENPN.{{cite journal | vauthors = Kixmoeller K, Allu PK, Black BE | title = The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle | journal = Open Biology | volume = 10 | issue = 6 | pages = 200051 | date = June 2020 | pmid = 32516549 | pmc = 7333888 | doi = 10.1098/rsob.200051 }}{{cite journal | vauthors = Yan K, Yang J, Zhang Z, McLaughlin SH, Chang L, Fasci D, Ehrenhofer-Murray AE, Heck AJ, Barford D | title = Structure of the inner kinetochore CCAN complex assembled onto a centromeric nucleosome | journal = Nature | volume = 574 | issue = 7777 | pages = 278–282 | date = October 2019 | pmid = 31578520 | pmc = 6859074 | doi = 10.1038/s41586-019-1609-1 | bibcode = 2019Natur.574..278Y }} Through this interaction the microtubules are able to accurately segregate chromosomes during mitosis.

{{reflist}}

• {{UCSC gene info|CENPA}}

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• {{cite journal | vauthors = Palmer DK, O'Day K, Trong HL, Charbonneau H, Margolis RL | title = Purification of the centromere-specific protein CENP-A and demonstration that it is a distinctive histone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 9 | pages = 3734–3738 | date = May 1991 | pmid = 2023923 | pmc = 51527 | doi = 10.1073/pnas.88.9.3734 | doi-access = free | bibcode = 1991PNAS...88.3734P }}
• {{cite journal | vauthors = Sullivan KF, Hechenberger M, Masri K | title = Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere | journal = The Journal of Cell Biology | volume = 127 | issue = 3 | pages = 581–592 | date = November 1994 | pmid = 7962047 | pmc = 2120219 | doi = 10.1083/jcb.127.3.581 }}
• {{cite journal | vauthors = Shelby RD, Vafa O, Sullivan KF | title = Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites | journal = The Journal of Cell Biology | volume = 136 | issue = 3 | pages = 501–513 | date = February 1997 | pmid = 9024683 | pmc = 2134286 | doi = 10.1083/jcb.136.3.501 }}
• {{cite journal | vauthors = Valdivia MM, Figueroa J, Iglesias C, Ortíz M | title = A novel centromere monospecific serum to a human autoepitope on the histone H3-like protein CENP-A | journal = FEBS Letters | volume = 422 | issue = 1 | pages = 5–9 | date = January 1998 | pmid = 9475158 | doi = 10.1016/S0014-5793(97)01583-4 | s2cid = 40104381 | doi-access = free }}
• {{cite journal | vauthors = Fowler KJ, Newson AJ, MacDonald AC, Kalitsis P, Lyu MS, Kozak CA, Choo KH | title = Chromosomal localization of mouse Cenpa gene | journal = Cytogenetics and Cell Genetics | volume = 79 | issue = 3–4 | pages = 298–301 | year = 1998 | pmid = 9605877 | doi = 10.1159/000134748 }}
• {{cite journal | vauthors = Muro Y, Azuma N, Onouchi H, Kunimatsu M, Tomita Y, Sasaki M, Sugimoto K | title = Autoepitopes on autoantigen centromere protein-A (CENP-A) are restricted to the N-terminal region, which has no homology with histone H3 | journal = Clinical and Experimental Immunology | volume = 120 | issue = 1 | pages = 218–223 | date = April 2000 | pmid = 10759786 | pmc = 1905620 | doi = 10.1046/j.1365-2249.2000.01189.x }}
• {{cite journal | vauthors = Lomonte P, Sullivan KF, Everett RD | title = Degradation of nucleosome-associated centromeric histone H3-like protein CENP-A induced by herpes simplex virus type 1 protein ICP0 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 8 | pages = 5829–5835 | date = February 2001 | pmid = 11053442 | doi = 10.1074/jbc.M008547200 | doi-access = free }}
• {{cite journal | vauthors = Uren AG, Wong L, Pakusch M, Fowler KJ, Burrows FJ, Vaux DL, Choo KH | title = Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype | journal = Current Biology | volume = 10 | issue = 21 | pages = 1319–1328 | date = November 2000 | pmid = 11084331 | doi = 10.1016/S0960-9822(00)00769-7 | s2cid = 18455745 | doi-access = free | bibcode = 2000CBio...10.1319U }}
• {{cite journal | vauthors = Zeitlin SG, Shelby RD, Sullivan KF | title = CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis | journal = The Journal of Cell Biology | volume = 155 | issue = 7 | pages = 1147–1157 | date = December 2001 | pmid = 11756469 | pmc = 2199334 | doi = 10.1083/jcb.200108125 }}
• {{cite journal | vauthors = Ando S, Yang H, Nozaki N, Okazaki T, Yoda K | title = CENP-A, -B, and -C chromatin complex that contains the I-type alpha-satellite array constitutes the prekinetochore in HeLa cells | journal = Molecular and Cellular Biology | volume = 22 | issue = 7 | pages = 2229–2241 | date = April 2002 | pmid = 11884609 | pmc = 133672 | doi = 10.1128/MCB.22.7.2229-2241.2002 }}
• {{cite journal | vauthors = Saxena A, Saffery R, Wong LH, Kalitsis P, Choo KH | title = Centromere proteins Cenpa, Cenpb, and Bub3 interact with poly(ADP-ribose) polymerase-1 protein and are poly(ADP-ribosyl)ated | journal = The Journal of Biological Chemistry | volume = 277 | issue = 30 | pages = 26921–26926 | date = July 2002 | pmid = 12011073 | doi = 10.1074/jbc.M200620200 | doi-access = free }}
• {{cite journal | vauthors = Figueroa J, Pendón C, Valdivia MM | title = Molecular cloning and sequence analysis of hamster CENP-A cDNA | journal = BMC Genomics | volume = 3 | pages = 11 | date = May 2002 | pmid = 12019018 | pmc = 113255 | doi = 10.1186/1471-2164-3-11 | doi-access = free }}
• {{cite journal | vauthors = Saxena A, Wong LH, Kalitsis P, Earle E, Shaffer LG, Choo KH | title = Poly(ADP-ribose) polymerase 2 localizes to mammalian active centromeres and interacts with PARP-1, Cenpa, Cenpb and Bub3, but not Cenpc | journal = Human Molecular Genetics | volume = 11 | issue = 19 | pages = 2319–2329 | date = September 2002 | pmid = 12217960 | doi = 10.1093/hmg/11.19.2319 | doi-access = free }}
• {{cite journal | vauthors = Tomonaga T, Matsushita K, Yamaguchi S, Oohashi T, Shimada H, Ochiai T, Yoda K, Nomura F | title = Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer | journal = Cancer Research | volume = 63 | issue = 13 | pages = 3511–3516 | date = July 2003 | pmid = 12839935 }}
• {{cite journal | vauthors = Kunitoku N, Sasayama T, Marumoto T, Zhang D, Honda S, Kobayashi O, Hatakeyama K, Ushio Y, Saya H, Hirota T | title = CENP-A phosphorylation by Aurora-A in prophase is required for enrichment of Aurora-B at inner centromeres and for kinetochore function | journal = Developmental Cell | volume = 5 | issue = 6 | pages = 853–864 | date = December 2003 | pmid = 14667408 | doi = 10.1016/S1534-5807(03)00364-2 | doi-access = free }}
• {{cite journal | vauthors = Obuse C, Yang H, Nozaki N, Goto S, Okazaki T, Yoda K | title = Proteomics analysis of the centromere complex from HeLa interphase cells: UV-damaged DNA binding protein 1 (DDB-1) is a component of the CEN-complex, while BMI-1 is transiently co-localized with the centromeric region in interphase | journal = Genes to Cells | volume = 9 | issue = 2 | pages = 105–120 | date = February 2004 | pmid = 15009096 | doi = 10.1111/j.1365-2443.2004.00705.x | s2cid = 21813024 | doi-access = free }}
• {{cite journal | vauthors = Yasuda S, Oceguera-Yanez F, Kato T, Okamoto M, Yonemura S, Terada Y, Ishizaki T, Narumiya S | title = Cdc42 and mDia3 regulate microtubule attachment to kinetochores | journal = Nature | volume = 428 | issue = 6984 | pages = 767–771 | date = April 2004 | pmid = 15085137 | doi = 10.1038/nature02452 | s2cid = 4401953 | bibcode = 2004Natur.428..767Y }}
• {{cite journal | vauthors = Black BE, Foltz DR, Chakravarthy S, Luger K, Woods VL, Cleveland DW | title = Structural determinants for generating centromeric chromatin | journal = Nature | volume = 430 | issue = 6999 | pages = 578–582 | date = July 2004 | pmid = 15282608 | doi = 10.1038/nature02766 | s2cid = 4392941 | bibcode = 2004Natur.430..578B }}
• {{cite journal | vauthors = Sullivan BA, Karpen GH | title = Centromeric chromatin exhibits a histone modification pattern that is distinct from both euchromatin and heterochromatin | journal = Nature Structural & Molecular Biology | volume = 11 | issue = 11 | pages = 1076–1083 | date = November 2004 | pmid = 15475964 | pmc = 1283111 | doi = 10.1038/nsmb845 }}
• {{cite journal | vauthors = Sekulic N, Bassett EA, Rogers DJ, Black BE | title = The structure of (CENP-A-H4)(2) reveals physical features that mark centromeres | journal = Nature | volume = 467 | issue = 7313 | pages = 347–351 | date = September 2010 | pmid = 20739937 | pmc = 2946842 | doi = 10.1038/nature09323 | bibcode = 2010Natur.467..347S }}

{{refend}}

{{Chromosome genetics}}