Alternative titles; symbols
HGNC Approved Gene Symbol: HASPIN
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:3,723,903-3,726,699 (from NCBI)
While examining transcription of the integrin alpha-E gene (ITGAE; 604682) in tissues that do not express ITGAE protein, Higgins (2001) identified the GSG2 gene, which they called haspin. Haspin is transcribed from the opposite strand of intron 26 of the ITGAE gene. By 5-prime RACE of testis total RNA, Higgins (2001) cloned haspin cDNA. The deduced 798-amino acid protein contains a C-terminal kinase domain and a potential nuclear localization signal. The mouse and human haspin proteins share 66% amino acid identity overall, with 83% identity in the C-terminal portion. Northern blot analysis detected a major 3.0-kb transcript and a minor 4.0-kb transcript in testis. Expression was also detected in adult thymus and bone marrow, with weaker expression in adult prostate, intestine, lung, spleen, and lymph node. Haspin expression was detected in fetal liver, skin, kidney, and small intestine, and in all proliferating cell lines tested, particularly in B- and T-cell lines. Expression was not detected in nonproliferating cells.
Using mouse haspin cDNA to probe a human testis cDNA library, Tanaka et al. (2001) cloned haspin. The deduced 798-amino acid protein has an N-terminal basic region, a C-terminal leucine zipper, and a protein kinase domain similar to CDC2 kinase (116940), as well as several potential phosphorylation sites. Northern blot analysis detected a major 2.8-kb transcript and a minor 4.2-kb transcript expressed exclusively in testis. Western blot analysis of human testis lysates detected a protein with an apparent molecular mass of 88 kD. Fluorescence-tagged haspin was expressed in punctate subnuclear foci in transfected human embryonic kidney cells.
By assaying human embryonic kidney cells transfected with haspin cDNA, Tanaka et al. (2001) demonstrated that haspin has protein kinase activity.
Histone H3 (see 602810) is phosphorylated on thr3 during prophase of mitotic cells, and it is dephosphorylated during anaphase. Dai et al. (2005) found that haspin phosphorylated H3 thr3 in human cell lines in vitro. Depletion of haspin by RNA interference revealed that haspin was required for H3 thr3 phosphorylation in mitotic cells. In addition to its chromosomal association, haspin associated with centrosomes and spindles during mitosis. Haspin RNA interference caused misalignment of metaphase chromosomes, and haspin overexpression delayed progression through early mitosis. Dai et al. (2005) concluded that haspin is a member of a group of kinases that integrate regulation of chromosome and spindle function during mitosis and meiosis.
Wang et al. (2010) showed that phosphorylation of histone H3 threonine-3 (H3T3ph) by haspin is necessary for chromosomal passenger complex (CPC) accumulation at centromeres and that the CPC subunit survivin (603352) binds directly to H3T3ph. A nonbinding survivin-D70A/D71A mutant did not support centromeric CPC concentration, and both haspin depletion and survivin-D70A/D71A mutation diminished centromere localization of the kinesin MCAK (604538) and the mitotic checkpoint response to taxol. Survivin-D70A/D71A mutation and microinjection of H3T3ph-specific antibody both compromised centromeric Aurora B (604970) functions but did not prevent cytokinesis. Therefore, Wang et al. (2010) concluded that H3T3ph generated by haspin positions the chromosomal passenger complex at centromeres to regulate selected targets of Aurora B during mitosis.
Kelly et al. (2010) demonstrated that H3T3ph is directly recognized by an evolutionarily conserved binding pocket in the BIR domain of the CPC subunit survivin. This binding mediates recruitment of the CPC to chromosomes and the resulting activation of its kinase subunit Aurora B. Consistently, modulation of the kinase activity of haspin, which phosphorylates H3T3, leads to defects in the Aurora B-dependent processes of spindle assembly and inhibition of nuclear reformation. Kelly et al. (2010) concluded that their findings established a direct cellular role for mitotic H3T3 phosphorylation, which is read and translated by the CPC to ensure accurate cell division.
Yamagishi et al. (2010) showed that phosphorylation of H3T3 mediated by haspin cooperates with bub1 (602452)-mediated histone 2A-serine-121 (H2A-S121) phosphorylation in targeting the CPC to the inner centromere in fission yeast and human cells. Phosphorylated H3T3 promotes nucleosome binding of survivin, whereas phosphorylated H2A-S121 facilitates the binding of shugoshin (609168), the centromeric CPC adaptor. Haspin colocalizes with cohesin by associating with Pds5 (see 613200), whereas bub1 localizes at kinetochores. Thus, Yamagishi et al. (2010) concluded that the inner centromere is defined by intersection of 2 histone kinases.
Higgins (2001) determined that haspin is an intronless gene transcribed from a bidirectional promoter that also generates an alternatively-spliced ITGAE transcript. The 5-prime end is surrounded by a CpG island, and the 3-prime UTR contains an Alu-J element. The promoter region contains binding sites for E2F (see 189971), AP2 (107580), and Sp1 (189906). The human and mouse haspin genes both have features of retroposons.
Higgins (2001) and Tanaka et al. (2001) mapped the haspin gene to chromosome 17p13, where it lies on the opposite strand within intron 26 of the ITGAE gene.
Dai, J., Sultan, S., Taylor, S. S., Higgins, J. M. G. The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment. Genes Dev. 19: 472-488, 2005. [PubMed: 15681610] [Full Text: https://doi.org/10.1101/gad.1267105]
Higgins, J. M. G. The haspin gene: location in an intron of the integrin alpha-E gene, associated transcription of an integrin alpha-E-derived RNA and expression in diploid as well as haploid cells. Gene 267: 55-69, 2001. [PubMed: 11311556] [Full Text: https://doi.org/10.1016/s0378-1119(01)00387-0]
Kelly, A. E., Ghenoiu, C., Xue, J. Z., Zierhut, C., Kimura, H., Funabiki, H. Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B. Science 330: 235-239, 2010. [PubMed: 20705815] [Full Text: https://doi.org/10.1126/science.1189505]
Tanaka, H., Iguchi, N., Nakamura, Y., Kohroki, J., Egydio de Carvalho, C., Nishimune, Y. Cloning and characterization of human haspin gene encoding haploid germ cell-specific nuclear protein kinase. Molec. Hum. Reprod. 7: 211-218, 2001. [PubMed: 11228240] [Full Text: https://doi.org/10.1093/molehr/7.3.211]
Wang, F., Dai, J., Daum, J. R., Niedzialkowska, E., Banerjee, B., Stukenberg, P. T., Gorbsky, G. J., Higgins, J. M. G. Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis. Science 330: 231-235, 2010. [PubMed: 20705812] [Full Text: https://doi.org/10.1126/science.1189435]
Yamagishi, Y., Honda, T., Tanno, Y., Watanabe, Y. Two histone marks establish the inner centromere and chromosome bi-orientation. Science 330: 239-233, 2010. [PubMed: 20929775] [Full Text: https://doi.org/10.1126/science.1194498]