Biology:CENPA

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Centromere protein A, also known as CENPA, is a protein which in humans is encoded by the CENPA gene.[1] CENPA is a histone H3 variant which is the critical factor determining the kinetochore position(s) on each chromosome[2] in most eukaryotes including humans.

Function

CENPA is a protein which epigenetically defines the position of the centromere on each chromosome,[3] 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.[4] The CENPA protein is a histone H3 variant which replaces one or both canonical H3 histones in a subset of nucleosomes within centromeric chromatin.[5][6] 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.[7]

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,[8] M phase in drosophila,[9] G2 in S. pombe.[10] To orchestrate this specialised loading there are CENPA-specific histone chaperones: HJURP in human, CAL1 in drosophila and Scm3 in S. pombe.[11] In most eukaryotes CENPA is loaded into large domains of highly repetitive satellite DNA.[12] The position of CENPA within satellite DNA are heritable at the protein level through a purely epigenetic mechanism.[13] 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.[14]

CENPA interacts directly with the inner kinetochore through proteins including CENPC and CENPN.[15][16] Through this interaction the microtubules are able to accurately segregate chromosomes during mitosis.

References

  1. ↑ EntrezGene 1058
  2. ↑ "Epigenetic regulation of centromeric chromatin: old dogs, new tricks?". Nature Reviews. Genetics 9 (12): 923–937. December 2008. doi:10.1038/nrg2466. PMID 19002142. 
  3. ↑ "A two-step mechanism for epigenetic specification of centromere identity and function". Nature Cell Biology 15 (9): 1056–1066. September 2013. doi:10.1038/ncb2805. PMID 23873148. 
  4. ↑ "Complete genomic and epigenetic maps of human centromeres". Science 376 (6588): eabl4178. April 2022. doi:10.1126/science.abl4178. PMID 35357911. 
  5. ↑ "Conserved organization of centromeric chromatin in flies and humans". Developmental Cell 2 (3): 319–330. March 2002. doi:10.1016/s1534-5807(02)00135-1. PMID 11879637. 
  6. ↑ "Human centromeric CENP-A chromatin is a homotypic, octameric nucleosome at all cell cycle points". The Journal of Cell Biology 216 (3): 607–621. March 2017. doi:10.1083/jcb.201608083. PMID 28235947. 
  7. ↑ "Posttranslational modifications of CENP-A: marks of distinction". Chromosoma 127 (3): 279–290. September 2018. doi:10.1007/s00412-018-0665-x. PMID 29569072. 
  8. ↑ "Propagation of centromeric chromatin requires exit from mitosis". The Journal of Cell Biology 176 (6): 795–805. March 2007. doi:10.1083/jcb.200701066. PMID 17339380. 
  9. ↑ "Incorporation of Drosophila CID/CENP-A and CENP-C into centromeres during early embryonic anaphase". Current Biology 17 (3): 237–243. February 2007. doi:10.1016/j.cub.2006.11.051. PMID 17222555. 
  10. ↑ "Centromere DNA Destabilizes H3 Nucleosomes to Promote CENP-A Deposition during the Cell Cycle". Current Biology 28 (24): 3924–3936.e4. December 2018. doi:10.1016/j.cub.2018.10.049. PMID 30503616. 
  11. ↑ "Histone chaperones: assisting histone traffic and nucleosome dynamics". Annual Review of Biochemistry 83: 487–517. 2014. doi:10.1146/annurev-biochem-060713-035536. PMID 24905786. 
  12. ↑ "Centromere identity from the DNA point of view". Chromosoma 123 (4): 313–325. August 2014. doi:10.1007/s00412-014-0462-0. PMID 24763964. 
  13. ↑ "Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles". Genome Research 26 (10): 1301–1311. October 2016. doi:10.1101/gr.206706.116. PMID 27510565. 
  14. ↑ "Centromeres: genetic input to calibrate an epigenetic feedback loop". The EMBO Journal 39 (20): e106638. October 2020. doi:10.15252/embj.2020106638. PMID 32959893. 
  15. ↑ "The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle". Open Biology 10 (6): 200051. June 2020. doi:10.1098/rsob.200051. PMID 32516549. 
  16. ↑ "Structure of the inner kinetochore CCAN complex assembled onto a centromeric nucleosome". Nature 574 (7777): 278–282. October 2019. doi:10.1038/s41586-019-1609-1. PMID 31578520. Bibcode: 2019Natur.574..278Y. 

External links

Further reading




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