CENPA
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCENPA, CENP-A, CenH3, centromere protein A
External IDsOMIM: 117139 MGI: 88375 HomoloGene: 1369 GeneCards: CENPA
Orthologs
SpeciesHumanMouse
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 MbChr 5: 30.82 – 30.83 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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. 1 2 3 GRCh38: Ensembl release 89: ENSG00000115163 - Ensembl, May 2017
  2. 1 2 3 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. 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. 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.

Further reading

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