Home LiteratureArticle Details
PMID: 10655499 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Early disruption of centromeric chromatin organization in centromere protein A (Cenpa) null mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 3 ·2000-02-01 ·Pages 1148-53

Howman EV, Fowler KJ, Newson AJ, Redward S, MacDonald AC, Kalitsis P, Choo KH

Abstract

Centromere protein A (Cenpa for mouse, CENP-A for other species) is a histone H3-like protein that is thought to be involved in the nucleosomal packaging of centromeric DNA. Using gene targeting, we have disrupted the mouse Cenpa gene and demonstrated that the gene is essential. Heterozygous mice are healthy and fertile whereas null mutants fail to survive beyond 6.5 days postconception. Affected embryos show severe mitotic problems, including micronuclei and macronuclei formation, nuclear bridging and blebbing, and chromatin fragmentation and hypercondensation. Immunofluorescence analysis of interphase cells at day 5.5 reveals complete Cenpa depletion, diffuse Cenpb foci, absence of discrete Cenpc signal on centromeres, and dispersion of Cenpb and Cenpc throughout the nucleus. These results suggest that Cenpa is essential for kinetochore targeting of Cenpc and plays an early role in organizing centromeric chromatin at interphase. The evidence is consistent with the proposal of a critical epigenetic function for CENP-A in marking a chromosomal region for centromere formation.

MeSH Terms
Animals Autoantigens Blastocyst/metabolism,pathology Centromere/metabolism,ultrastructure Centromere Protein A Centromere Protein B Chromatin/metabolism,ultrastructure Chromosomal Proteins, Non-Histone/deficiency,genetics,metabolism,physiology DNA-Binding Proteins Gene Targeting Genes, Lethal Genotype Interphase Mice Mice, Knockout Microscopy, Fluorescence
Chemicals
Autoantigens Cenpa protein, mouse Cenpb protein, mouse Centromere Protein A Centromere Protein B Chromatin Chromosomal Proteins, Non-Histone DNA-Binding Proteins centromere protein C
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Howman E V
The Murdoch Institute, Royal Children's Hospital, Flemington Road, Parkville 3052, Australia.
Fowler K J
Newson A J
Redward S
MacDonald A C
Kalitsis P
Choo K H
References (41)
41 references, click to expand
  1. The structure of the mammalian centromere.
    Bioessays. 1991 Feb;13(2):51-6 PMID: 2029266
  2. Cell redundancy in the zona-intact preimplantation mouse blastocyst: a light and electron microscope study of dead cells and their fate.
    J Embryol Exp Morphol. 1974 Jun;31(3):643-54 PMID: 4448942
  3. CENP-C, an autoantigen in scleroderma, is a component of the human inner kinetochore plate.
    Cell. 1992 Jul 10;70(1):115-25 PMID: 1339310
  4. Histone H3 N-terminal mutations allow hyperactivation of the yeast GAL1 gene in vivo.
    EMBO J. 1992 Sep;11(9):3297-306 PMID: 1505519
  5. MIF2 is required for mitotic spindle integrity during anaphase spindle elongation in Saccharomyces cerevisiae.
    J Cell Biol. 1993 Oct;123(2):387-403 PMID: 8408221
  6. CENP-C is required for maintaining proper kinetochore size and for a timely transition to anaphase.
    J Cell Biol. 1994 May;125(3):531-45 PMID: 8175879
  7. Dicistronic targeting constructs: reporters and modifiers of mammalian gene expression.
    Proc Natl Acad Sci U S A. 1994 May 10;91(10):4303-7 PMID: 8183905
  8. Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere.
    J Cell Biol. 1994 Nov;127(3):581-92 PMID: 7962047
  9. A mutation in CSE4, an essential gene encoding a novel chromatin-associated protein in yeast, causes chromosome nondisjunction and cell cycle arrest at mitosis.
    Genes Dev. 1995 Mar 1;9(5):573-86 PMID: 7698647
  10. Further evidence that CENP-C is a necessary component of active centromeres: studies of a dic(X; 15) with simultaneous immunofluorescence and FISH.
    Hum Mol Genet. 1995 Feb;4(2):289-94 PMID: 7757082
  11. Is there a unique form of chromatin at the Saccharomyces cerevisiae centromeres?
    Bioessays. 1995 Aug;17(8):669-72 PMID: 7661847
  12. Identification of overlapping DNA-binding and centromere-targeting domains in the human kinetochore protein CENP-C.
    Mol Cell Biol. 1996 Jul;16(7):3576-86 PMID: 8668174
  13. Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites.
    J Cell Biol. 1997 Feb 10;136(3):501-13 PMID: 9024683
  14. Chromosomal proteins and cytokinesis: patterns of cleavage furrow formation and inner centromere protein positioning in mitotic heterokaryons and mid-anaphase cells.
    J Cell Biol. 1997 Mar 24;136(6):1169-83 PMID: 9087435
  15. A functional neo-centromere formed through activation of a latent human centromere and consisting of non-alpha-satellite DNA.
    Nat Genet. 1997 Jun;16(2):144-53 PMID: 9171825
  16. Efficient conditional mutation of the vertebrate CENP-C gene.
    Hum Mol Genet. 1997 Dec;6(13):2301-8 PMID: 9361037
  17. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation.
    Chromosoma. 1997 Nov;106(6):348-60 PMID: 9362543
  18. The case for epigenetic effects on centromere identity and function.
    Trends Genet. 1997 Dec;13(12):489-96 PMID: 9433139
  19. Targeted disruption of mouse centromere protein C gene leads to mitotic disarray and early embryo death.
    Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1136-41 PMID: 9448298
  20. Gene structure and sequence analysis of mouse centromere proteins A and C.
    Genomics. 1998 Jan 1;47(1):108-14 PMID: 9465302
  21. A novel centromere monospecific serum to a human autoepitope on the histone H3-like protein CENP-A.
    FEBS Lett. 1998 Jan 23;422(1):5-9 PMID: 9475158
  22. Centromere protein B null mice are mitotically and meiotically normal but have lower body and testis weights.
    J Cell Biol. 1998 Apr 20;141(2):309-19 PMID: 9548711
  23. Centromeric chromatin and epigenetic effects in kinetochore assembly.
    Cell. 1998 May 1;93(3):313-6 PMID: 9590163
  24. Something from nothing: the evolution and utility of satellite repeats.
    Trends Genet. 1998 May;14(5):200-4 PMID: 9613205
  25. The vertebrate cell kinetochore and its roles during mitosis.
    Trends Cell Biol. 1998 Aug;8(8):310-8 PMID: 9704407
  26. Cse4p is a component of the core centromere of Saccharomyces cerevisiae.
    Cell. 1998 Sep 4;94(5):607-13 PMID: 9741625
  27. Centromeric protein B null mice are viable with no apparent abnormalities.
    Dev Biol. 1998 Sep 15;201(2):135-43 PMID: 9740654
  28. Microinjection of antibodies to centromere protein CENP-A arrests cells in interphase but does not prevent mitosis.
    Chromosoma. 1998 Dec;107(6-7):397-405 PMID: 9914371
  29. Mammalian centromeres: DNA sequence, protein composition, and role in cell cycle progression.
    Exp Cell Res. 1999 Feb 1;246(2):249-62 PMID: 9925740
  30. Kinetochores and the checkpoint mechanism that monitors for defects in the chromosome segregation machinery.
    Annu Rev Genet. 1998;32:307-37 PMID: 9928483
  31. The cenpB gene is not essential in mice.
    Chromosoma. 1998 Dec;107(8):570-6 PMID: 9933410
  32. Sequence analysis of an 80 kb human neocentromere.
    Hum Mol Genet. 1999 Feb;8(2):217-27 PMID: 9931329
  33. The spindle checkpoint.
    Curr Opin Genet Dev. 1999 Feb;9(1):69-75 PMID: 10072359
  34. Centromere proteins and chromosome inheritance: a complex affair.
    Curr Opin Genet Dev. 1999 Apr;9(2):206-17 PMID: 10322137
  35. Defective chromosome segregation, microtubule bundling and nuclear bridging in inner centromere protein gene (Incenp)-disrupted mice.
    Hum Mol Genet. 1999 Jul;8(7):1145-55 PMID: 10369859
  36. CENP-C is necessary but not sufficient to induce formation of a functional centromere.
    EMBO J. 1999 Aug 2;18(15):4196-209 PMID: 10428958
  37. Conservation of centromere protein in vertebrates.
    Chromosome Res. 1999;7(4):261-5 PMID: 10461871
  38. Construction of a small Mus musculus repetitive DNA library: identification of a new satellite sequence in Mus musculus.
    Nucleic Acids Res. 1983 Oct 25;11(20):6965-83 PMID: 6314268
  39. Visualization of centromere proteins CENP-B and CENP-C on a stable dicentric chromosome in cytological spreads.
    Chromosoma. 1989 Jun;98(1):1-12 PMID: 2475307
  40. Purification of the centromere-specific protein CENP-A and demonstration that it is a distinctive histone.
    Proc Natl Acad Sci U S A. 1991 May 1;88(9):3734-8 PMID: 2023923
  41. The nucleosomal core histone octamer at 3.1 A resolution: a tripartite protein assembly and a left-handed superhelix.
    Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10148-52 PMID: 1946434
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.97.3.1148
Published
2000-02-01
Pages
1148-53
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC15551
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.97.3.1148 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2