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. The CENPA protein is a histone H3 variant which replaces one or both canonical H3 histones in a subset of nucleosomes within centromeric chromatin.[8][9] 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.[10]
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,[11]M phase in drosophila,[12]G2 in S. pombe.[13] To orchestrate this specialised loading there are CENPA-specific histone chaperones: HJURP in human, CAL1 in drosophila and Scm3 in S. pombe.[14] In most eukaryotes CENPA is loaded into large domains of highly repetitive satellite DNA.[15] The position of CENPA within satellite DNA are heritable at the protein level through a purely epigenetic mechanism.[16] 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.[17]
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Uren AG, Wong L, Pakusch M, Fowler KJ, Burrows FJ, Vaux DL, Choo KH (November 2000). "Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype". Current Biology. 10 (21): 1319–28. doi:10.1016/S0960-9822(00)00769-7. PMID11084331. S2CID18455745.
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): 3511–6. PMID12839935.
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): 853–64. doi:10.1016/S1534-5807(03)00364-2. PMID14667408.
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): 105–20. doi:10.1111/j.1365-2443.2004.00705.x. PMID15009096. S2CID21813024.
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): 767–71. doi:10.1038/nature02452. PMID15085137. S2CID4401953.
Black BE, Foltz DR, Chakravarthy S, Luger K, Woods VL, Cleveland DW (July 2004). "Structural determinants for generating centromeric chromatin". Nature. 430 (6999): 578–82. doi:10.1038/nature02766. PMID15282608. S2CID4392941.
