CENPA

CENPA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3AN2, 3NQJ, 3NQU, 3R45, 3WTP, 5CVD
Identifiers
Aliases	CENPA, CENP-A, CenH3, centromere protein A
External IDs	OMIM: 117139; MGI: 88375; HomoloGene: 1369; GeneCards: CENPA; OMA:CENPA - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p23.3 Start 26,764,289 bp[1] End 26,801,067 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 B1|5 16.76 cM Start 30,824,121 bp[2] End 30,832,174 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in oocyte secondary oocyte gonad ventricular zone buccal mucosa cell ganglionic eminence testicle thymus trabecular bone bone marrow Top expressed in endocardial cushion ventricular zone renal corpuscle medial ganglionic eminence maxillary prominence mandibular prominence abdominal wall primitive streak otic placode tail of embryo More reference expression data BioGPS n/a
Gene ontology Molecular function DNA binding chromatin binding protein binding protein heterodimerization activity nucleosomal DNA binding Cellular component inner kinetochore cytosol nucleoplasm chromosome chromosome, centromeric region nucleus kinetochore nucleosome Biological process CENP-A containing chromatin assembly establishment of mitotic spindle orientation protein localization to chromosome, centromeric region viral process kinetochore assembly sister chromatid cohesion mitotic cytokinesis cell cycle cell division nucleosome assembly Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1058 12615 Ensembl ENSG00000115163 ENSMUSG00000029177 UniProt P49450 O35216 RefSeq (mRNA) NM_001809 NM_001042426 NM_007681 NM_001302129 NM_001302130 NM_001302131 NM_001302132 RefSeq (protein) NP_001035891 NP_001800 NP_001289058 NP_001289059 NP_001289060 NP_001289061 NP_031707 Location (UCSC) Chr 2: 26.76 – 26.8 Mb Chr 5: 30.82 – 30.83 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Centromere protein A, also known as CENPA, is a protein which in humans is encoded by the CENPA gene.^[5] CENPA is a histone H3 variant which is the critical factor determining the kinetochore position(s) on each chromosome^[6] in most eukaryotes including humans.

Function

CENPA is a protein which epigenetically defines the position of the centromere on each chromosome,^[7] 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.^[8] The CENPA protein is a histone H3 variant which replaces one or both canonical H3 histones in a subset of nucleosomes within centromeric chromatin.^[9][10] 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.^[11]

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,^[12] M phase in drosophila,^[13] G2 in S. pombe.^[14] To orchestrate this specialised loading there are CENPA-specific histone chaperones: HJURP in human, CAL1 in drosophila and Scm3 in S. pombe.^[15] In most eukaryotes CENPA is loaded into large domains of highly repetitive satellite DNA.^[16] The position of CENPA within satellite DNA are heritable at the protein level through a purely epigenetic mechanism.^[17] 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.^[18]

CENPA interacts directly with the inner kinetochore through proteins including CENPC and CENPN.^[19][20] Through this interaction the microtubules are able to accurately segregate chromosomes during mitosis.

References

1. GRCh38: Ensembl release 89: ENSG00000115163 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029177 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. EntrezGene 1058
6. Allshire RC, Karpen GH (December 2008). "Epigenetic regulation of centromeric chromatin: old dogs, new tricks?". Nature Reviews. Genetics. 9 (12): 923–937. doi:10.1038/nrg2466. PMC 2586333. PMID 19002142.
7. Fachinetti D, Folco HD, Nechemia-Arbely Y, Valente LP, Nguyen K, Wong AJ, et al. (September 2013). "A two-step mechanism for epigenetic specification of centromere identity and function". Nature Cell Biology. 15 (9): 1056–1066. doi:10.1038/ncb2805. PMC 4418506. PMID 23873148.
8. Altemose N, Logsdon GA, Bzikadze AV, Sidhwani P, Langley SA, Caldas GV, et al. (April 2022). "Complete genomic and epigenetic maps of human centromeres". Science. 376 (6588) eabl4178. doi:10.1126/science.abl4178. PMC 9233505. PMID 35357911.
9. Blower MD, Sullivan BA, Karpen GH (March 2002). "Conserved organization of centromeric chromatin in flies and humans". Developmental Cell. 2 (3): 319–330. doi:10.1016/s1534-5807(02)00135-1. PMC 3192492. PMID 11879637.
10. Nechemia-Arbely Y, Fachinetti D, Miga KH, Sekulic N, Soni GV, Kim DH, et al. (March 2017). "Human centromeric CENP-A chromatin is a homotypic, octameric nucleosome at all cell cycle points". The Journal of Cell Biology. 216 (3): 607–621. doi:10.1083/jcb.201608083. PMC 5350519. PMID 28235947.
11. Srivastava S, Foltz DR (September 2018). "Posttranslational modifications of CENP-A: marks of distinction". Chromosoma. 127 (3): 279–290. doi:10.1007/s00412-018-0665-x. PMC 6082721. PMID 29569072.
12. Jansen LE, Black BE, Foltz DR, Cleveland DW (March 2007). "Propagation of centromeric chromatin requires exit from mitosis". The Journal of Cell Biology. 176 (6): 795–805. doi:10.1083/jcb.200701066. PMC 2064054. PMID 17339380.
13. Schuh M, Lehner CF, Heidmann S (February 2007). "Incorporation of Drosophila CID/CENP-A and CENP-C into centromeres during early embryonic anaphase". Current Biology. 17 (3): 237–243. Bibcode:2007CBio...17..237S. doi:10.1016/j.cub.2006.11.051. hdl:11858/00-001M-0000-002A-23E4-7. PMID 17222555. S2CID 17907028.
14. Shukla M, Tong P, White SA, Singh PP, Reid AM, Catania S, et al. (December 2018). "Centromere DNA Destabilizes H3 Nucleosomes to Promote CENP-A Deposition during the Cell Cycle". Current Biology. 28 (24): 3924–3936.e4. Bibcode:2018CBio...28E3924S. doi:10.1016/j.cub.2018.10.049. PMC 6303189. PMID 30503616.
15. Gurard-Levin ZA, Quivy JP, Almouzni G (2014). "Histone chaperones: assisting histone traffic and nucleosome dynamics". Annual Review of Biochemistry. 83: 487–517. doi:10.1146/annurev-biochem-060713-035536. PMID 24905786.
16. Plohl M, Meštrović N, Mravinac B (August 2014). "Centromere identity from the DNA point of view". Chromosoma. 123 (4): 313–325. doi:10.1007/s00412-014-0462-0. PMC 4107277. PMID 24763964.
17. Aldrup-MacDonald ME, Kuo ME, Sullivan LL, Chew K, Sullivan BA (October 2016). "Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles". Genome Research. 26 (10): 1301–1311. doi:10.1101/gr.206706.116. PMC 5052062. PMID 27510565.
18. van den Berg SJ, Jansen LE (October 2020). "Centromeres: genetic input to calibrate an epigenetic feedback loop". The EMBO Journal. 39 (20) e106638. doi:10.15252/embj.2020106638. PMC 7560195. PMID 32959893.
19. Kixmoeller K, Allu PK, Black BE (June 2020). "The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle". Open Biology. 10 (6) 200051. doi:10.1098/rsob.200051. PMC 7333888. PMID 32516549.
20. Yan K, Yang J, Zhang Z, McLaughlin SH, Chang L, Fasci D, et al. (October 2019). "Structure of the inner kinetochore CCAN complex assembled onto a centromeric nucleosome". Nature. 574 (7777): 278–282. Bibcode:2019Natur.574..278Y. doi:10.1038/s41586-019-1609-1. PMC 6859074. PMID 31578520.

External links

• Human CENPA genome location and CENPA gene details page in the UCSC Genome Browser.

Further reading

• Palmer DK, O'Day K, Trong HL, Charbonneau H, Margolis RL (May 1991). "Purification of the centromere-specific protein CENP-A and demonstration that it is a distinctive histone". Proceedings of the National Academy of Sciences of the United States of America. 88 (9): 3734–3738. Bibcode:1991PNAS...88.3734P. doi:10.1073/pnas.88.9.3734. PMC 51527. PMID 2023923.
• Sullivan KF, Hechenberger M, Masri K (November 1994). "Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere". The Journal of Cell Biology. 127 (3): 581–592. doi:10.1083/jcb.127.3.581. PMC 2120219. PMID 7962047.
• Shelby RD, Vafa O, Sullivan KF (February 1997). "Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites". The Journal of Cell Biology. 136 (3): 501–513. doi:10.1083/jcb.136.3.501. PMC 2134286. PMID 9024683.
• Valdivia MM, Figueroa J, Iglesias C, Ortíz M (January 1998). "A novel centromere monospecific serum to a human autoepitope on the histone H3-like protein CENP-A". FEBS Letters. 422 (1): 5–9. doi:10.1016/S0014-5793(97)01583-4. PMID 9475158. S2CID 40104381.
• Fowler KJ, Newson AJ, MacDonald AC, Kalitsis P, Lyu MS, Kozak CA, et al. (1998). "Chromosomal localization of mouse Cenpa gene". Cytogenetics and Cell Genetics. 79 (3–4): 298–301. doi:10.1159/000134748. PMID 9605877.
• Muro Y, Azuma N, Onouchi H, Kunimatsu M, Tomita Y, Sasaki M, et al. (April 2000). "Autoepitopes on autoantigen centromere protein-A (CENP-A) are restricted to the N-terminal region, which has no homology with histone H3". Clinical and Experimental Immunology. 120 (1): 218–223. doi:10.1046/j.1365-2249.2000.01189.x. PMC 1905620. PMID 10759786.
• Lomonte P, Sullivan KF, Everett RD (February 2001). "Degradation of nucleosome-associated centromeric histone H3-like protein CENP-A induced by herpes simplex virus type 1 protein ICP0". The Journal of Biological Chemistry. 276 (8): 5829–5835. doi:10.1074/jbc.M008547200. PMID 11053442.
• Uren AG, Wong L, Pakusch M, Fowler KJ, Burrows FJ, Vaux DL, et al. (November 2000). "Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype". Current Biology. 10 (21): 1319–1328. Bibcode:2000CBio...10.1319U. doi:10.1016/S0960-9822(00)00769-7. PMID 11084331. S2CID 18455745.
• Zeitlin SG, Shelby RD, Sullivan KF (December 2001). "CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis". The Journal of Cell Biology. 155 (7): 1147–1157. doi:10.1083/jcb.200108125. PMC 2199334. PMID 11756469.
• Ando S, Yang H, Nozaki N, Okazaki T, Yoda K (April 2002). "CENP-A, -B, and -C chromatin complex that contains the I-type alpha-satellite array constitutes the prekinetochore in HeLa cells". Molecular and Cellular Biology. 22 (7): 2229–2241. doi:10.1128/MCB.22.7.2229-2241.2002. PMC 133672. PMID 11884609.
• Saxena A, Saffery R, Wong LH, Kalitsis P, Choo KH (July 2002). "Centromere proteins Cenpa, Cenpb, and Bub3 interact with poly(ADP-ribose) polymerase-1 protein and are poly(ADP-ribosyl)ated". The Journal of Biological Chemistry. 277 (30): 26921–26926. doi:10.1074/jbc.M200620200. PMID 12011073.
• Figueroa J, Pendón C, Valdivia MM (May 2002). "Molecular cloning and sequence analysis of hamster CENP-A cDNA". BMC Genomics. 3: 11. doi:10.1186/1471-2164-3-11. PMC 113255. PMID 12019018.
• Saxena A, Wong LH, Kalitsis P, Earle E, Shaffer LG, Choo KH (September 2002). "Poly(ADP-ribose) polymerase 2 localizes to mammalian active centromeres and interacts with PARP-1, Cenpa, Cenpb and Bub3, but not Cenpc". Human Molecular Genetics. 11 (19): 2319–2329. doi:10.1093/hmg/11.19.2319. PMID 12217960.
• Tomonaga T, Matsushita K, Yamaguchi S, Oohashi T, Shimada H, Ochiai T, et al. (July 2003). "Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer". Cancer Research. 63 (13): 3511–3516. PMID 12839935.
• Kunitoku N, Sasayama T, Marumoto T, Zhang D, Honda S, Kobayashi O, et al. (December 2003). "CENP-A phosphorylation by Aurora-A in prophase is required for enrichment of Aurora-B at inner centromeres and for kinetochore function". Developmental Cell. 5 (6): 853–864. doi:10.1016/S1534-5807(03)00364-2. PMID 14667408.
• Obuse C, Yang H, Nozaki N, Goto S, Okazaki T, Yoda K (February 2004). "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". Genes to Cells. 9 (2): 105–120. doi:10.1111/j.1365-2443.2004.00705.x. PMID 15009096. S2CID 21813024.
• Yasuda S, Oceguera-Yanez F, Kato T, Okamoto M, Yonemura S, Terada Y, et al. (April 2004). "Cdc42 and mDia3 regulate microtubule attachment to kinetochores". Nature. 428 (6984): 767–771. Bibcode:2004Natur.428..767Y. doi:10.1038/nature02452. PMID 15085137. S2CID 4401953.
• Black BE, Foltz DR, Chakravarthy S, Luger K, Woods VL, Cleveland DW (July 2004). "Structural determinants for generating centromeric chromatin". Nature. 430 (6999): 578–582. Bibcode:2004Natur.430..578B. doi:10.1038/nature02766. PMID 15282608. S2CID 4392941.
• Sullivan BA, Karpen GH (November 2004). "Centromeric chromatin exhibits a histone modification pattern that is distinct from both euchromatin and heterochromatin". Nature Structural & Molecular Biology. 11 (11): 1076–1083. doi:10.1038/nsmb845. PMC 1283111. PMID 15475964.
• Sekulic N, Bassett EA, Rogers DJ, Black BE (September 2010). "The structure of (CENP-A-H4)(2) reveals physical features that mark centromeres". Nature. 467 (7313): 347–351. Bibcode:2010Natur.467..347S. doi:10.1038/nature09323. PMC 2946842. PMID 20739937.