Skip to main content
SpringerLink
Log in

Centromere DNA, proteins and kinetochore assembly in vertebrate cells

  • Published:
Chromosome Research Aims and scope Submit manuscript

Abstract

The centromere is a specialized region of the chromosome that is essential for faithful chromosome segregation during mitosis and meiosis in eukaryotic cells. It is the site at which the kinetochore, the functional nucleoprotein complex responsible for microtubule binding and chromosome movement, is assembled through complex molecular mechanisms. Herein, I review recent advances in our understanding of centromeric DNAs as sites for kinetochore assembly and the mechanisms underlying kinetochore assembly in vertebrate cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ahmad K, Henikoff S (2002) The histone variant H3.3 marks active chromatin by replication-independent nucleosome assembly. Mol Cell 9: 1191–1200.

    Article  PubMed  CAS  Google Scholar 

  • Bharadwaj R, Qi W, Yu H (2004) Identification of two novel components of the human Ndc80 kinetochore complex. J Biol Chem 279: 13076–13085.

    Article  PubMed  CAS  Google Scholar 

  • Blower MD, Karpen GH (2001) The role of Drosophila CID in kinetochore formation, cell-cycle progression and heterochromatin interactions. Nat Cell Biol 3: 730–739.

    Article  PubMed  CAS  Google Scholar 

  • Blower MD, Sullivan BA, Karpen GH (2002) Conserved organization of centromeric chromatin in flies and humans. Dev Cell 2: 319–330.

    Article  PubMed  CAS  Google Scholar 

  • Brown MT, Goetsch L, Hartwell LH (1993) MIF2 is required for mitotic integrity during anaphase spindle elongation in Sacchromyces cerevisiae. J Cell Biol 123: 387–403.

    Article  PubMed  CAS  Google Scholar 

  • Brown WR, Mee PJ, Shen MH (2000) Artificial chromosomes: ideal vectors? Trends Biotechnol 18: 218–223.

    Article  PubMed  CAS  Google Scholar 

  • Brown WR, Hubbard SJ, Tickle C, Wilson SA (2003) The chicken as a model for large-scale analysis of vertebrate gene function. Nat Rev Genet 4: 87–98.

    Article  PubMed  CAS  Google Scholar 

  • Cahill DP, Lengauer C, Yu J et al.(1998) Mutations of mitotic checkpoint genes in human cancers. Nature 392: 300–303.

    Article  PubMed  CAS  Google Scholar 

  • Carmena M, Earnshaw WC (2003) The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 4: 842–854.

    Article  PubMed  CAS  Google Scholar 

  • Chen ES, Saitoh S, Yanagida M, Takahashi K (2003) A cell cycle-regulated GATA factor promotes centromeric localization of CENP-A in fission yeast. Mol Cell 11: 175–187.

    Article  PubMed  CAS  Google Scholar 

  • Choo KH (2001) Domain organization at centromere and neocentromere. Dev Cell 1: 165–177.

    Article  PubMed  CAS  Google Scholar 

  • Cleveland DW, Mao Y, Sullivan KF (2003) Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112: 407–421.

    Article  PubMed  CAS  Google Scholar 

  • Compton DA, Yen TJ, Cleveland DW (1991) Identification of novel centromere/kinetochore-associated proteins using monoclonal antibodies generated against human mitotic chromosome scaffolds. J Cell Biol 112: 1083–1097.

    Article  PubMed  CAS  Google Scholar 

  • Craig JM, Earnshaw WC, Vagnarelli P (1999) Mammalian centromeres: DNA sequence, protein composition, and role in cell cycle progression. Exp Cell Res 246: 249–262.

    Article  PubMed  CAS  Google Scholar 

  • DeLuca JG, Howell BJ, Canman JC, Hickey JM, Fang G, Salmon ED (2003) Nuf2 and Hec1 are required for retention of the checkpoint proteins Mad1 and Mad2 to kinetochores. Curr Biol 13: 2103–2109.

    Article  PubMed  CAS  Google Scholar 

  • Floridia G, Zatterale A, Zuffardi O, Tyler-Smith C (2000) Mapping of a human centromere onto the DNA by topoisomerase II cleavage. EMBO Rep 1: 489–493.

    PubMed  CAS  Google Scholar 

  • Fukagawa T, Brown WRA (1997) Efficient conditional mutation of the vertebrate CENP-C gene. Hum Mol Genet 6: 2301–2308.

    Article  PubMed  CAS  Google Scholar 

  • Fukagawa T, Pendon C, Morris J, Brown W (1999) CENP-C is necessary but not sufficient to induce formation of functional centromere. EMBO J 18: 4196–4209.

    Article  PubMed  CAS  Google Scholar 

  • Fukagawa T, Mikami Y, Nishihashi A et al.(2001) CENP-H, a constitutive centromere component, is required for centromere targeting of CENP-C in vertebrate cells. EMBO J 20: 4603–4617.

    Article  PubMed  CAS  Google Scholar 

  • Goshima G, Saitoh S, Yanagida M (1999) Proper metaphase spindle length is determined by centromere proteins Mis12 and Mis6 required for faithful chromosome segregation. Genes Dev 13: 1664–1677.

    PubMed  CAS  Google Scholar 

  • Goshima G, Kiyomitsu T, Yoda K, Yanagida M (2003) Human centromere chromatin protein hMis12, essential for equal segregation, is independent of CENP-A loading pathway. J Cell Biol 160: 25–39.

    Article  PubMed  CAS  Google Scholar 

  • Hall IM, Noma K, Grewal SI (2003) RNA interference machinery regulates chromosome dynamics during mitosis and meiosis in fission yeast. Proc Natl Acad Sci USA 100: 193–198.

    Article  PubMed  CAS  Google Scholar 

  • Harrington JJ, Van Bokkelen G, Mays RW, Gustashaw K, Willard HF (1997) Formation of de novo centromeres and construction of first-generation human artificial microchromosomes. Nat Genet 15: 345–355.

    Article  PubMed  CAS  Google Scholar 

  • Hori T, Haraguchi T, Hiraoka Y, Kimura H, Fukagawa, T (2003) Dynamic behavior of Nuf2-Hec1 complex that localizes to the centrosome and centromere and is essential for mitotic progression in vertebrate cells. J Cell Sci 116: 3347–3362.

    Article  PubMed  CAS  Google Scholar 

  • Howman EV, Fowler KJ, Newson AJ et al.(2000) Early disruption of centromeric chromatin organization in centromere protein A (Cenpa) null mice. Proc Natl Acad Sci USA 97: 1148–1153.

    Article  PubMed  CAS  Google Scholar 

  • Hudson DF, Fowler KJ, Earle E et al.(1998) Centromere protein B null mice are mitotically and meiotically normal but have lower body and testis weights. J Cell Biol 141: 309–319.

    Article  PubMed  CAS  Google Scholar 

  • Ikeno M, Grimes B, Okazaki T et al.(1998) Construction of YAC-based mammalian artificial chromosomes. Nat Biotechnol 16: 431–439.

    Article  PubMed  CAS  Google Scholar 

  • Janke C, Ortiz Jhechner et al.(2001) The budding yeast proteins Spc24p and Spc25p interact with Ndc80p and Nuf2p at the kinetochore and are important for kinetochore clustering and checkpoint control. EMBO J 20: 777–791.

    Article  PubMed  CAS  Google Scholar 

  • Kalitsis P, Fowler KJ, Earle E, Hill J, Choo KHA (1998) Targeted disruption of mouse centromere protein C gene leads to mitotic disarray and early embryo death. Proc Natl Acad Sci USA 95: 576–582.

    Article  Google Scholar 

  • Kallio M, Weinstein J, Daurn JR, Burke DJ, Gorbsky GJ (1998) Mammalian p55CDC mediates association of the spindle checkpoint protein Mad2 with the cyclosome/ anaphase-promoting complex, and is involved in regulating anaphase onset and late mitotic events. J Cell Biol 141: 1393–1406.

    Article  PubMed  CAS  Google Scholar 

  • Kallio MJ, Beardmore VA, Weinstein J, Gorbsky GJ (2002) Rapid microtubule-independent dynamics of Cdc20 at kinetochores and centrosomes in mammalian cells. J Cell Biol 158: 841–847.

    Article  PubMed  CAS  Google Scholar 

  • Karpen GH, Allshire, RC (1997) The case for epigenetic effects on centromere identity and function. Trends Genet 13: 489–496

    Article  PubMed  CAS  Google Scholar 

  • Liu ST, Hittle JC, Jablonski SA, Campbell MS, Yoda K, Yen TJ (2003) Human CENP-I specifies localization of CENP-F, MAD1 and MAD2 to kinetochores and is essential for mitosis. Nat Cell Biol 5:341–345

    Article  PubMed  CAS  Google Scholar 

  • Malik HS, Henikoff S (2002) Conflict begets complexity: the evolution of centromeres. Curr Opin Genet Dev 12: 711–718.

    Article  PubMed  CAS  Google Scholar 

  • Martin-Lluesma S, Stucke VM, Nigg EA (2002) Role of Hec1 in spindle checkpoint signaling and kinetochore recruitment of Mad1/Mad2. Science 297: 2267–2270.

    Article  PubMed  CAS  Google Scholar 

  • Masumoto H, Masukata H, Muro Y, Nozaki N, Okazaki T (1989) A human centromere antigen (CENP-B) interacts with a short specific sequence in alphoid DNA, a human centromeric satellite. J Cell Biol 109: 1963–1973.

    Article  PubMed  CAS  Google Scholar 

  • McCleland ML, Kallio MJ, Barrett-Wilt GA et al.(2004) The vertebrate Ndc80 complex contains Spc24 and Spc25 homologs, which are required to establish and maintain kinetochore-microtubule attachment. Curr Biol 14: 131–137.

    Article  PubMed  CAS  Google Scholar 

  • Measday V, Hailey DW, Pot I et al.(2002) Ctf3, the Mis6 budding yeast homolog, interacts with Mcm22p and Mcm16p at the yeast outer kinetochore. Genes Dev 16: 101–113.

    Article  PubMed  CAS  Google Scholar 

  • Mellone BG, Allshire RC (2003) Stretching it: putting the CEN(P-A) in centromere. Curr Opin Cell Biol 13: 191–198.

    CAS  Google Scholar 

  • Meluh PB, Koshland D (1995) Evidence that the Mif2 gene of Saccharomyces cerevisiae encodes a centromere protein with homology to the mammalian centromere protein CENP-C. Mol Biol Cell 6: 793–807.

    PubMed  CAS  Google Scholar 

  • Moroi Y, Peebles C, Fritzler MJ, Steigerwald J, Tan EM (1980) Autoantibody to centromere (kinetochore) in scleroderma sera. Proc Natl Acad Sci USA 77: 1627–1631.

    Article  PubMed  CAS  Google Scholar 

  • Nakagawa H, Lee JK, Hurwitz J et al.(2002) Fission yeast CENP-B homologs nucleate centromeric heterochromatin by promoting heterochromatin-specific histone tail modifications. Genes Dev 16: 1766–1778.

    Article  PubMed  CAS  Google Scholar 

  • Nishihashi A, Haraguchi T, Hiraoka Y et al.(2002) CENP-I is essential for centromere function in vertebrate cells. Dev Cell 2: 463–476.

    Article  PubMed  CAS  Google Scholar 

  • Ohzeki J, Nakano M, Okada T, Masumoto H (2002) CENP-B box is required for de novo centromere chromatin assembly on human alphoid DNA. J Cell Biol 159: 765–775.

    Article  PubMed  CAS  Google Scholar 

  • Palmer DK, Margolis RL (1987) A 17-kD centromere protein (CENP-A) copurifies with nucleosome core particles and with histones. J Cell Biol 104: 805–815.

    Article  PubMed  CAS  Google Scholar 

  • Partridge JF, Scott KS, Bannister AJ, Kouzarides T, Allshire RC (2002) cis-acting DNA from fission yeast centromeres mediates histone H3 methylation and recruitment of silencing factors and cohesin to an ectopic site. Curr Biol 12: 1652–1660.

    Article  PubMed  CAS  Google Scholar 

  • Pluta AF, Mackay AM, Ainsztein AM, Goldberg IG, Earnshaw WC (1995) The centromere: Hub of chromosomal activities. Science 270: 1591–1594.

    PubMed  CAS  Google Scholar 

  • Provost P, Silverstein RA, Dishart D et al.(2002) Dicer is required for chromosome segregation and gene silencing in fission yeast cells. Proc Natl Acad Sci USA 99: 16648–16653.

    Article  PubMed  CAS  Google Scholar 

  • Ray-Gallet D, Quivy JP, Scamps C, Martini EM, Lipinski M, Almouzni G (2002) HIRA is critical for a nucleosome assembly pathway independent of DNA synthesis. Mol Cell 9: 1091–1100.

    Article  PubMed  CAS  Google Scholar 

  • Saitoh H, Tomkiel J, Cooke CA et al.(1992) CENP-C, an autoantigen in scleroderma, is a component of the human inner kinetochore plate. Cell 70: 115–125.

    Article  PubMed  CAS  Google Scholar 

  • Saitoh S, Takahashi K, Yanagida M (1997) Mis6, a fission yeast inner centromere protein, acts during G1/S and forms specialized chromatin required for equal segregation. Cell 90: 131–143.

    Article  PubMed  CAS  Google Scholar 

  • Shelby RD, Vafa O, Sullivan KF (1997) Assembly of CENP-A into centromere chromatin requires a cooperative array of nucleosomal DNA contact sites. J Cell Biol 136: 501–513.

    Article  PubMed  CAS  Google Scholar 

  • Spence JM, Critcher R, Ebersole TA et al.(2002) Co-localization of centromere activity, proteins and topoisomerase II within a subdomain of the major human X alpha-satellite array. EMBO J 21: 5269–5280.

    Article  PubMed  CAS  Google Scholar 

  • Sugata N, Munekata E, Todokoro K (1999) Characterization of a novel kinetochore protein, CENP-H. J Biol Chem 274: 27343–27346.

    Article  PubMed  CAS  Google Scholar 

  • Sugata N, Li S, Earnshaw WC et al. (2000) Human CENP-H multimers colocalize with CENP-A and CENP-C at active centromere-kinetochore complexes. Hum Mol Genet 9: 2919–2926.

    Article  PubMed  CAS  Google Scholar 

  • Sullivan BA (2002) Centromere round-up at the heterochromatin corral. Trends Biotechnol 20: 89–92.

    Article  PubMed  CAS  Google Scholar 

  • Sullivan BA, Schwartz S (1995) Identification of centromeric antigens in dicentric Robertsonian translocations: CENP-C and CENP-E are necessary components of functional centromeres. Hum Mol Genet 4: 2189–2197.

    PubMed  CAS  Google Scholar 

  • Sullivan BA, Blower MD, Karpen GH (2001) Determining centromere identity: cyclical stories and forking path. Nat Rev Genet 2: 584–596.

    Article  PubMed  CAS  Google Scholar 

  • Sullivan KF (2001) A solid foundation: functional specialization of centromeric chromatin. Curr Opin Genet Dev 11: 182–188.

    Article  PubMed  CAS  Google Scholar 

  • Tagami H, Ray-Gallet D, Almouzni G, Nakatani Y (2004) Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 116: 51–61.

    Article  PubMed  CAS  Google Scholar 

  • Takahashi K, Chen ES, Yanagida M (2000) Requirement of Mis6 centromere connector for localizing a CENP-A-like protein in fission yeast. Science 288: 2215–2219.

    Article  PubMed  CAS  Google Scholar 

  • Tomkiel J, Cooke CA, Saitoh H, Bernat RL, Earnshaw WC (1994) CENP-C is required for maintaining proper kinetochore size and for a timely transition to anaphase. J Cell Biol 125: 531–545.

    Article  PubMed  CAS  Google Scholar 

  • Volpe TA, Kidner C, Hall IM, Teng G, Grewal SI, Martienssen RA (2002) Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297: 1833–1837.

    Article  PubMed  CAS  Google Scholar 

  • Volpe T, Schramke V, Hamilton GL et al.(2003) RNA interference is required for normal centromere function in fission yeast. Chromosome Res 11: 137–146.

    Article  PubMed  CAS  Google Scholar 

  • Warburton PE, Cooke CA, Bourassa S et al.(1997) Immunolocalization of CENP-A suggests a novel nucleosome structure at the inner kinetochore plate of active centromeres. Curr Biol 7: 901–904.

    Article  PubMed  CAS  Google Scholar 

  • Wiens GR, Soger PK (1998) Centromeric chromatin and epigenetic effects in kinetochore assembly. Cell 93: 313–316.

    Article  PubMed  CAS  Google Scholar 

  • Wigge PA, Kilmartin JV (2001) The Ndc80p complex from Saccharomyces cerevisiae contains conserved centromere components and has a function in chromosome segregation. J Cell Biol 152: 349–360.

    Article  PubMed  CAS  Google Scholar 

  • Yang CH, Tomkiel J, Saitoh H, Johnson DH, Earnshaw WC (1996) Identification of overlapping DNA-binding and centromere-targeting domains in the human kinetochore protein CENP-C. Mol Cell Biol 16: 3576–3586.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. PRESTO, the Japan Science and Technology Agency (JST), National Institute of Genetics and The Graduate University for Advanced Studies, Mishima, Shizuoka, 411-8540, Japan; Tel

    Tatsuo Fukagawa

Authors
  1. Tatsuo Fukagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fukagawa, T. Centromere DNA, proteins and kinetochore assembly in vertebrate cells. Chromosome Res 12, 557–567 (2004). https://doi.org/10.1023/B:CHRO.0000036590.96208.83

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:CHRO.0000036590.96208.83

Search

Navigation