Skip to main content
Log in

At the right place at the right time: novel CENP-A binding proteins shed light on centromere assembly

  • Mini-Review
  • Published:
Chromosoma Aims and scope Submit manuscript

Abstract

Centromeres, the chromosomal loci that form the sites of attachment for spindle microtubules during mitosis, are identified by a unique chromatin structure generated by nucleosomes containing the histone H3 variant CENP-A. The apparent epigenetic mode of centromere inheritance across mitotic and meiotic divisions has generated much interest in how CENP-A assembly occurs and how structurally divergent centromeric nucleosomes can specify the centromere complex. Although a substantial number of proteins have been implicated in centromere assembly, factors that can bind CENP-A specifically and deliver nascent protein to the centromere were, thus far, lacking. Several recent reports on experiments in fission yeast and human cells have now shown significant progress on this problem. Here, we discuss these new developments and their implications for epigenetic centromere inheritance.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Allshire RC, Karpen GH (2008) Epigenetic regulation of centromeric chromatin: old dogs, new tricks? Nat Rev Genet 9:923–937

    Article  PubMed  CAS  Google Scholar 

  • Amor DJ, Bentley K, Ryan J, Perry J, Wong L, Slater H, Choo KH (2004) Human centromere repositioning "in progress". Proc Natl Acad Sci USA 101:6542–6547

    Article  PubMed  CAS  Google Scholar 

  • Aravind L, Iyer LM, Wu C (2007) Domain architectures of the Scm3p protein provide insights into centromere function and evolution. Cell cycle (Georgetown. Tex 6:2511–2515

    CAS  Google Scholar 

  • Black BE, Foltz DR, Chakravarthy S, Luger K, Woods VL Jr, Cleveland DW (2004) Structural determinants for generating centromeric chromatin. Nature 430:578–582

    Article  PubMed  CAS  Google Scholar 

  • Black BE, Brock MA, Bedard S, Woods VL Jr, Cleveland DW (2007a) An epigenetic mark generated by the incorporation of CENP-A into centromeric nucleosomes. Proc Natl Acad Sci USA 104:5008–5013

    Article  PubMed  CAS  Google Scholar 

  • Black BE, Jansen LE, Maddox PS, Foltz DR, Desai AB, Shah JV, Cleveland DW (2007b) Centromere identity maintained by nucleosomes assembled with histone H3 containing the CENP-A targeting domain. Mol Cell 25:309–322

    Article  PubMed  CAS  Google Scholar 

  • Boyer LA, Latek RR, Peterson CL (2004) The SANT domain: a unique histone-tail-binding module? Nat Rev Mol Cell Biol 5:158–163

    Article  PubMed  CAS  Google Scholar 

  • Carroll CW, Silva MCC, Godek KM, Jansen LET, Straight AF (2009) Centromere assembly requires the direct recognition of CENP-A nucleosomes by CENP-N. Nat Cell Biol. 21 June 2009; doi:10.1038/ncb1899

  • Cheeseman IM, Desai A (2008) Molecular architecture of the kinetochore-microtubule interface. Nat Rev Mol Cell Biol 9:33–46

    Article  PubMed  CAS  Google Scholar 

  • Cheeseman IM, Drubin DG, Barnes G (2002) Simple centromere, complex kinetochore: linking spindle microtubules and centromeric DNA in budding yeast. J Cell Biol 157:199–203

    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 

  • 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 

  • Dalal Y (2009) Epigenetic specification of centromeres. Biochem Cell Biol 87:273–282

    Article  PubMed  CAS  Google Scholar 

  • Dunleavy EM, Pidoux AL, Monet M, Bonilla C, Richardson W, Hamilton GL, Ekwall K, McLaughlin PJ, Allshire RC (2007) A NASP (N1/N2)-related protein, Sim3, binds CENP-A and is required for its deposition at fission yeast centromeres. Mol Cell 28:1029–1044

    Article  PubMed  CAS  Google Scholar 

  • Dunleavy EM, Roche D, Tagami H, Lacoste N, Ray-Gallet D, Nakamura Y, Daigo Y, Nakatani Y, Almouzni-Pettinotti G (2009) HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres. Cell 137:485–497

    Article  PubMed  CAS  Google Scholar 

  • Erhardt S, Mellone BG, Betts CM, Zhang W, Karpen GH, Straight AF (2008) Genome-wide analysis reveals a cell cycle-dependent mechanism controlling centromere propagation. J Cell Biol 183:805–818

    Article  PubMed  CAS  Google Scholar 

  • Foltz DR, Jansen LE, Black BE, Bailey AO, Yates JR 3rd, Cleveland DW (2006) The human CENP-A centromeric nucleosome-associated complex. Nat Cell Biol 8:458–469

    Article  PubMed  CAS  Google Scholar 

  • Foltz DR, Jansen LE, Bailey AO, Yates JR 3rd, Bassett EA, Wood S, Black BE, Cleveland DW (2009) Centromere-specific assembly of CENP-a nucleosomes is mediated by HJURP. Cell 137:472–484

    Article  PubMed  CAS  Google Scholar 

  • Fujita Y, Hayashi T, Kiyomitsu T, Toyoda Y, Kokubu A, Obuse C, Yanagida M (2007) Priming of Centromere for CENP-A Recruitment by Human hMis18alpha, hMis18beta, and M18BP1. Dev Cell 12:17–30

    Article  PubMed  CAS  Google Scholar 

  • Fukagawa T, De Wulf P (2009) Kinetochore composition, formation and organization. In: De Wulf P, Earnshaw WC (eds) The Kinetochore: from molecular discoveries to cancer therapy. Springer, New York, pp 133–191

    Google Scholar 

  • Furuyama T, Dalal Y, Henikoff S (2006) Chaperone-mediated assembly of centromeric chromatin in vitro. Proc Natl Acad Sci USA 103:6172–6177

    Article  PubMed  CAS  Google Scholar 

  • Hayashi T, Fujita Y, Iwasaki O, Adachi Y, Takahashi K, Yanagida M (2004) Mis16 and Mis18 are required for CENP-A loading and histone deacetylation at centromeres. Cell 118:715–729

    Article  PubMed  CAS  Google Scholar 

  • Hemmerich P, Weidtkamp-Peters S, Hoischen C, Schmiedeberg L, Erliandri I, Diekmann S (2008) Dynamics of inner kinetochore assembly and maintenance in living cells. J Cell Biol 180:1101–1114

    Article  PubMed  CAS  Google Scholar 

  • Heun P, Erhardt S, Blower MD, Weiss S, Skora AD, Karpen GH (2006) Mislocalization of the Drosophila centromere-specific histone CID promotes formation of functional ectopic kinetochores. Dev Cell 10:303–315

    Article  PubMed  CAS  Google Scholar 

  • Hori T, Amano M, Suzuki A, Backer CB, Welburn JP, Dong Y, McEwen BF, Shang WH, Suzuki E, Okawa K et al (2008) CCAN makes multiple contacts with centromeric DNA to provide distinct pathways to the outer kinetochore. Cell 135:1039–1052

    Article  PubMed  CAS  Google Scholar 

  • Ishii K, Ogiyama Y, Chikashige Y, Soejima S, Masuda F, Kakuma T, Hiraoka Y, Takahashi K (2008) Heterochromatin integrity affects chromosome reorganization after centromere dysfunction. Science 321:1088–1091

    Article  PubMed  CAS  Google Scholar 

  • Izuta H, Ikeno M, Suzuki N, Tomonaga T, Nozaki N, Obuse C, Kisu Y, Goshima N, Nomura F, Nomura N et al (2006) Comprehensive analysis of the ICEN (Interphase Centromere Complex) components enriched in the CENP-A chromatin of human cells. Genes Cells 11:673–684

    Article  PubMed  CAS  Google Scholar 

  • Jansen LE, Black BE, Foltz DR, Cleveland DW (2007) Propagation of centromeric chromatin requires exit from mitosis. J Cell Biol 176:795–805

    Article  PubMed  CAS  Google Scholar 

  • Kato T, Sato N, Hayama S, Yamabuki T, Ito T, Miyamoto M, Kondo S, Nakamura Y, Daigo Y (2007) Activation of Holliday junction recognizing protein involved in the chromosomal stability and immortality of cancer cells. Cancer Res 67:8544–8553

    Article  PubMed  CAS  Google Scholar 

  • Kline SL, Cheeseman IM, Hori T, Fukagawa T, Desai A (2006) The human Mis12 complex is required for kinetochore assembly and proper chromosome segregation. J Cell Biol 173:9–17

    Article  PubMed  CAS  Google Scholar 

  • LeRoy G, Orphanides G, Lane WS, Reinberg D (1998) Requirement of RSF and FACT for transcription of chromatin templates in vitro. Science 282:1900–1904

    Article  PubMed  CAS  Google Scholar 

  • Liu ST, Rattner JB, Jablonski SA, Yen TJ (2006) Mapping the assembly pathways that specify formation of the trilaminar kinetochore plates in human cells. J Cell Biol 175:41–53

    Article  PubMed  CAS  Google Scholar 

  • Maddox PS, Hyndman F, Monen J, Oegema K, Desai A (2007) Functional genomics identifies a Myb domain-containing protein family required for assembly of CENP-A chromatin. J Cell Biol 176:757–763

    Article  PubMed  CAS  Google Scholar 

  • McClelland SE, Borusu S, Amaro AC, Winter JR, Belwal M, McAinsh AD, Meraldi P (2007) The CENP-A NAC/CAD kinetochore complex controls chromosome congression and spindle bipolarity. EMBO J 26:5033–5047

    Article  PubMed  CAS  Google Scholar 

  • Mizuguchi G, Xiao H, Wisniewski J, Smith MM, Wu C (2007) Nonhistone Scm3 and histones CenH3–H4 assemble the core of centromere-specific nucleosomes. Cell 129:1153–1164

    Article  PubMed  CAS  Google Scholar 

  • Okada M, Cheeseman IM, Hori T, Okawa K, McLeod IX, Yates JR 3rd, Desai A, Fukagawa T (2006) The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres. Nat Cell Biol 8:446–457

    Article  PubMed  CAS  Google Scholar 

  • Palmer DK, O'Day K, Wener MH, Andrews BS, 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 

  • Perpelescu M, Nozaki N, Obuse C, Yang H, Yoda K (2009) Active establishment of centromeric CENP-A chromatin by RSF complex. J Cell Biol 185:397–407

    Article  PubMed  CAS  Google Scholar 

  • Pidoux AL, Richardson W, Allshire RC (2003) Sim4: a novel fission yeast kinetochore protein required for centromeric silencing and chromosome segregation. J Cell Biol 161:295–307

    Article  PubMed  CAS  Google Scholar 

  • Pidoux AL, Choi ES, Abbott JK, Liu X, Kagansky A, Castillo AG, Hamilton GL, Richardson W, Rappsilber J, He X et al (2009) Fission yeast Scm3: A CENP-A receptor required for integrity of subkinetochore chromatin. Molecular cell 33:299–311

    Article  PubMed  CAS  Google Scholar 

  • Regnier V, Vagnarelli P, Fukagawa T, Zerjal T, Burns E, Trouche D, Earnshaw W, Brown W (2005) CENP-A is required for accurate chromosome segregation and sustained kinetochore association of BubR1. Mol Cell Biol 25:3967–3981

    Article  PubMed  CAS  Google Scholar 

  • Schuh M, Lehner CF, Heidmann S (2007) Incorporation of Drosophila CID/CENP-A and CENP-C into centromeres during early embryonic anaphase. Curr Biol 17:237–243

    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 

  • Takahashi K, Takayama Y, Masuda F, Kobayashi Y, Saitoh S (2005) Two distinct pathways responsible for the loading of CENP-A to centromeres in the fission yeast cell cycle. Philos Trans R Soc Lond 360:595–606 discussion 606–597

    Article  CAS  Google Scholar 

  • Verreault A, Kaufman PD, Kobayashi R, Stillman B (1996) Nucleosome assembly by a complex of CAF-1 and acetylated histones H3/H4. Cell 87:95–104

    Article  PubMed  CAS  Google Scholar 

  • Walfridsson J, Bjerling P, Thalen M, Yoo EJ, Park SD, Ekwall K (2005) The CHD remodeling factor Hrp1 stimulates CENP-A loading to centromeres. Nucleic Acids Res 33:2868–2879

    Article  PubMed  CAS  Google Scholar 

  • Warburton PE (2004) Chromosomal dynamics of human neocentromere formation. Chromosome Res 12:617–626

    Article  PubMed  CAS  Google Scholar 

  • Williams JS, Hayashi T, Yanagida M, Russell P (2009) Fission yeast Scm3 mediates stable assembly of Cnp1/CENP-A into centromeric chromatin. Molecular cell 33:287–298

    Article  PubMed  CAS  Google Scholar 

  • Yoda K, Ando S, Morishita S, Houmura K, Hashimoto K, Takeyasu K, Okazaki T (2000) Human centromere protein A (CENP-A) can replace histone H3 in nucleosome reconstitution in vitro. Proc Natl Acad Sci USA 97:7266–7271

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dan Foltz and Ben Black for suggestions and discussion and Iain Cheeseman for the LAP-hMis18α construct. We are indebted to Don Cleveland in whose laboratory the LAP-hMis18α/CENP-A-SNAP double tagged line was built. MCCS is supported by the Fundação para a Ciência e Tecnologia (FCT) (SFRH/BD/33219/2007). LETJ is supported by FCT, Fundação Calouste Gulbenkian, the EU Seventh Framework Program (FP7) and by an EMBO installation grant.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lars E. T. Jansen.

Additional information

Communicated by E.A. Nigg

Rights and permissions

Reprints and permissions

About this article

Cite this article

Silva, M.C.C., Jansen, L.E.T. At the right place at the right time: novel CENP-A binding proteins shed light on centromere assembly. Chromosoma 118, 567–574 (2009). https://doi.org/10.1007/s00412-009-0227-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00412-009-0227-3

Keywords

Navigation