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PMID: 17101789 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

HP1 proteins are essential for a dynamic nuclear response that rescues the function of perturbed heterochromatin in primary human cells.

Molecular and cellular biology ·Vol. 27 ·No. 3 ·2007-02-00 ·Pages 949-62

Zhang R, Liu ST, Chen W, Bonner M, Pehrson J, Yen TJ, Adams PD

Abstract

Cellular information is encoded genetically in the DNA nucleotide sequence and epigenetically by the "histone code," DNA methylation, and higher-order packaging of DNA into chromatin. Cells possess intricate mechanisms to sense and repair damage to DNA and the genetic code. However, nothing is known of the mechanisms, if any, that repair and/or compensate for damage to epigenetically encoded information, predicted to result from perturbation of DNA and histone modifications or other changes in chromatin structure. Here we show that primary human cells respond to a variety of small molecules that perturb DNA and histone modifications by recruiting HP1 proteins to sites of altered pericentromeric heterochromatin. This response is essential to maintain the HP1-binding kinetochore protein hMis12 at kinetochores and to suppress catastrophic mitotic defects. Recruitment of HP1 proteins to pericentromeres depends on histone H3.3 variant deposition, mediated by the HIRA histone chaperone. These data indicate that defects in pericentromeric epigenetic heterochromatin modifications initiate a dynamic HP1-dependent response that rescues pericentromeric heterochromatin function and is essential for viable progression through mitosis.

MeSH Terms
Cell Cycle Proteins/metabolism Cell Nucleus/drug effects,genetics,metabolism Cells, Cultured Centromere/drug effects,metabolism Chromobox Protein Homolog 5 Chromosomal Proteins, Non-Histone/metabolism Fibroblasts/cytology,drug effects Heterochromatin/drug effects,metabolism Histone Chaperones Histones/metabolism Humans Hydroxamic Acids/pharmacology Molecular Chaperones/metabolism Protein Transport/drug effects Transcription Factors/metabolism
Chemicals
Cell Cycle Proteins Chromosomal Proteins, Non-Histone HIRA protein, human Heterochromatin Histone Chaperones Histones Hydroxamic Acids Molecular Chaperones Transcription Factors macroH2A histone Chromobox Protein Homolog 5 trichostatin A
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Zhang Rugang
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Liu Song-tao
Chen Wei
Bonner Michael
Pehrson John
Yen Timothy J
Adams Peter D
References (73)
73 references, click to expand
  1. Changes in nucleosomal core histone variants during chicken development and maturation.
    Dev Biol. 1983 Feb;95(2):421-8 PMID: 6825941
  2. Regulation of nucleosomal core histone variant levels in differentiating murine erythroleukemia cells.
    Biochemistry. 1984 Sep 11;23(19):4436-43 PMID: 6593094
  3. Specific alterations in the pattern of histone-3 synthesis during conversion of human leukemic cells to terminally differentiated cells in culture.
    Differentiation. 1984;28(2):186-90 PMID: 6597116
  4. Three human chromosomal autoantigens are recognized by sera from patients with anti-centromere antibodies.
    J Clin Invest. 1986 Feb;77(2):426-30 PMID: 3511098
  5. Changes in the levels of three different classes of histone mRNA during murine erythroleukemia cell differentiation.
    Mol Cell Biol. 1985 Nov;5(11):2879-86 PMID: 3018484
  6. Modulation of histone H3 variant synthesis during the myoblast-myotube transition of chicken myogenesis.
    Dev Biol. 1987 Jan;119(1):94-9 PMID: 3792638
  7. Reversible arrest of proliferation of rat 3Y1 fibroblasts in both the G1 and G2 phases by trichostatin A.
    Exp Cell Res. 1988 Jul;177(1):122-31 PMID: 3134246
  8. Induction of H3.3 replacement histone mRNAs during the precommitment period of murine erythroleukemia cell differentiation.
    Nucleic Acids Res. 1993 Jun 25;21(12):2873-9 PMID: 8332496
  9. Conservation of deposition-related acetylation sites in newly synthesized histones H3 and H4.
    Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1237-41 PMID: 7862667
  10. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors.
    Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3697-702 PMID: 15738394
  11. Transcriptional activation triggers deposition and removal of the histone variant H3.3.
    Genes Dev. 2005 Apr 1;19(7):804-14 PMID: 15774717
  12. Changes in core histone variant composition in differentiating neurons: the roles of differential turnover and synthesis rates.
    Eur J Cell Biol. 1995 Nov;68(3):220-5 PMID: 8603674
  13. Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines.
    Nature. 1996 Sep 19;383(6597):269-72 PMID: 8805705
  14. Rad51 expression and localization in B cells carrying out class switch recombination.
    Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10222-7 PMID: 8816780
  15. Analysis of chromatin structure by in vivo formaldehyde cross-linking.
    Methods. 1997 Feb;11(2):205-14 PMID: 8993033
  16. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage.
    Cell. 1997 Aug 8;90(3):425-35 PMID: 9267023
  17. hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks.
    Mol Cell Biol. 1997 Oct;17(10):6087-96 PMID: 9315668
  18. Disruption of higher-order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III.
    Mol Cell Biol. 1998 Aug;18(8):4629-38 PMID: 9671473
  19. PTMs on H3 variants before chromatin assembly potentiate their final epigenetic state.
    Mol Cell. 2006 Oct 20;24(2):309-16 PMID: 17052464
  20. Changes in histones H2A and H3 variant composition in differentiating and mature rat brain cortical neurons.
    Dev Biol. 1987 Sep;123(1):51-8 PMID: 3622934
  21. Histone variants of H2A and H3 families are regulated during in vitro aging in the same manner as during differentiation.
    Exp Gerontol. 1999 Sep;34(6):741-54 PMID: 10579635
  22. Human centromeres and neocentromeres show identical distribution patterns of >20 functionally important kinetochore-associated proteins.
    Hum Mol Genet. 2000 Jan 22;9(2):175-85 PMID: 10607828
  23. Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells.
    Mol Biol Cell. 2000 Jun;11(6):2069-83 PMID: 10848630
  24. Molecular determinants for targeting heterochromatin protein 1-mediated gene silencing: direct chromoshadow domain-KAP-1 corepressor interaction is essential.
    Mol Cell Biol. 2000 Sep;20(17):6449-65 PMID: 10938122
  25. Reversible disruption of pericentric heterochromatin and centromere function by inhibiting deacetylases.
    Nat Cell Biol. 2001 Feb;3(2):114-20 PMID: 11175742
  26. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins.
    Nature. 2001 Mar 1;410(6824):116-20 PMID: 11242053
  27. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain.
    Nature. 2001 Mar 1;410(6824):120-4 PMID: 11242054
  28. Hir proteins are required for position-dependent gene silencing in Saccharomyces cerevisiae in the absence of chromatin assembly factor I.
    Mol Cell Biol. 1998 Aug;18(8):4793-806 PMID: 9671489
  29. Localization and phosphorylation of HP1 proteins during the cell cycle in mammalian cells.
    Chromosoma. 1999 Aug;108(4):220-34 PMID: 10460410
  30. A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1.
    Nat Cell Biol. 2004 Nov;6(11):1135-41 PMID: 15502821
  31. Cell-cycle checkpoints and cancer.
    Nature. 2004 Nov 18;432(7015):316-23 PMID: 15549093
  32. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA.
    Dev Cell. 2005 Jan;8(1):19-30 PMID: 15621527
  33. Cancer epigenetics.
    Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R65-76 PMID: 15809275
  34. Inhibitors of histone deacetylases alter kinetochore assembly by disrupting pericentromeric heterochromatin.
    Cell Cycle. 2005 May;4(5):717-26 PMID: 15846093
  35. Histone H3 lysine 9 methylation and HP1gamma are associated with transcription elongation through mammalian chromatin.
    Mol Cell. 2005 Aug 5;19(3):381-91 PMID: 16061184
  36. Variant histone H3.3 is deposited at sites of nucleosomal displacement throughout transcribed genes while active histone modifications show a promoter-proximal bias.
    Genes Dev. 2005 Aug 1;19(15):1761-6 PMID: 16077006
  37. Genome-scale profiling of histone H3.3 replacement patterns.
    Nat Genet. 2005 Oct;37(10):1090-7 PMID: 16155569
  38. The histone H3.3 chaperone HIRA is essential for chromatin assembly in the male pronucleus.
    Nature. 2005 Oct 27;437(7063):1386-90 PMID: 16251970
  39. Maize rough sheath2 and its Arabidopsis orthologue ASYMMETRIC LEAVES1 interact with HIRA, a predicted histone chaperone, to maintain knox gene silencing and determinacy during organogenesis.
    Plant Cell. 2005 Nov;17(11):2886-98 PMID: 16243907
  40. Expression patterns and post-translational modifications associated with mammalian histone H3 variants.
    J Biol Chem. 2006 Jan 6;281(1):559-68 PMID: 16267050
  41. Organization of interphase chromatin.
    Chromosoma. 2006 Feb;115(1):1-14 PMID: 16362820
  42. Hip3 interacts with the HIRA proteins Hip1 and Slm9 and is required for transcriptional silencing and accurate chromosome segregation.
    J Biol Chem. 2006 Mar 31;281(13):8732-9 PMID: 16428807
  43. Histone H3.3 variant dynamics in the germline of Caenorhabditis elegans.
    PLoS Genet. 2006 Jun;2(6):e97 PMID: 16846252
  44. HIRA, the human homologue of yeast Hir1p and Hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression.
    Mol Cell Biol. 2001 Mar;21(5):1854-65 PMID: 11238922
  45. p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2.
    EMBO J. 2001 Mar 15;20(6):1331-40 PMID: 11250899
  46. MACROH2A2, a new member of the MARCOH2A core histone family.
    J Biol Chem. 2001 Jun 15;276(24):21776-84 PMID: 11262398
  47. Yeast histone deposition protein Asf1p requires Hir proteins and PCNA for heterochromatic silencing.
    Curr Biol. 2001 Apr 3;11(7):463-73 PMID: 11412995
  48. Rb targets histone H3 methylation and HP1 to promoters.
    Nature. 2001 Aug 2;412(6846):561-5 PMID: 11484059
  49. Specificity of the HP1 chromo domain for the methylated N-terminus of histone H3.
    EMBO J. 2001 Sep 17;20(18):5232-41 PMID: 11566886
  50. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.
    Cell. 2001 Oct 19;107(2):149-59 PMID: 11672523
  51. Chromatin assembly factor I mutants defective for PCNA binding require Asf1/Hir proteins for silencing.
    Mol Cell Biol. 2002 Jan;22(2):614-25 PMID: 11756556
  52. Chromatin assembly factor I and Hir proteins contribute to building functional kinetochores in S. cerevisiae.
    Genes Dev. 2002 Jan 1;16(1):85-100 PMID: 11782447
  53. Epigenetic codes for heterochromatin formation and silencing: rounding up the usual suspects.
    Cell. 2002 Feb 22;108(4):489-500 PMID: 11909520
  54. Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component.
    Nat Genet. 2002 Mar;30(3):329-34 PMID: 11850619
  55. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells.
    Science. 2002 May 10;296(5570):1132-6 PMID: 12004135
  56. The histone variant H3.3 marks active chromatin by replication-independent nucleosome assembly.
    Mol Cell. 2002 Jun;9(6):1191-200 PMID: 12086617
  57. Coordinated methyl and RNA binding is required for heterochromatin localization of mammalian HP1alpha.
    EMBO Rep. 2002 Oct;3(10):975-81 PMID: 12231507
  58. Maintenance of stable heterochromatin domains by dynamic HP1 binding.
    Science. 2003 Jan 31;299(5607):721-5 PMID: 12560555
  59. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.
    Cell. 2003 Jun 13;113(6):703-16 PMID: 12809602
  60. Histone hyperacetylation in mitosis prevents sister chromatid separation and produces chromosome segregation defects.
    Mol Biol Cell. 2003 Sep;14(9):3821-33 PMID: 12972566
  61. Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis.
    Cell. 2004 Jan 9;116(1):51-61 PMID: 14718166
  62. Histone H3.3 is enriched in covalent modifications associated with active chromatin.
    Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1525-30 PMID: 14732680
  63. The Schizosaccharomyces pombe HIRA-like protein Hip1 is required for the periodic expression of histone genes and contributes to the function of complex centromeres.
    Mol Cell Biol. 2004 May;24(10):4309-20 PMID: 15121850
  64. Beyond the double helix: writing and reading the histone code.
    Novartis Found Symp. 2004;259:3-17; discussion 17-21, 163-9 PMID: 15171244
  65. Bromodomains in living cells participate in deciphering the histone code.
    Trends Cell Biol. 2004 Jun;14(6):279-81 PMID: 15183183
  66. Localized domains of G9a-mediated histone methylation are required for silencing of neuronal genes.
    Mol Cell. 2004 Jun 18;14(6):727-38 PMID: 15200951
  67. RNA interference demonstrates a novel role for H2A.Z in chromosome segregation.
    Nat Struct Mol Biol. 2004 Jul;11(7):650-5 PMID: 15195148
  68. Nuclear organization of centromeric domains is not perturbed by inhibition of histone deacetylases.
    Chromosome Res. 2004;12(5):505-16 PMID: 15254368
  69. The butyrate story: old wine in new bottles?
    Curr Opin Clin Nutr Metab Care. 2004 Sep;7(5):563-7 PMID: 15295277
  70. Analysis of the centromeric regions of the human genome assembly.
    Trends Genet. 2004 Nov;20(11):529-33 PMID: 15475110
  71. The dynamic kinetochore-microtubule interface.
    J Cell Sci. 2004 Nov 1;117(Pt 23):5461-77 PMID: 15509863
  72. X-ray sensitivity of fifty-three human diploid fibroblast cell strains from patients with characterized genetic disorders.
    Cancer Res. 1980 Mar;40(3):920-5 PMID: 7471105
  73. Survey of radiosensitivity in a variety of human cell strains.
    Cancer Res. 1980 Mar;40(3):926-32 PMID: 7471106
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.01639-06
Published
2007-02-00
Epub
2006-00-13
Pages
949-62
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1800672
Subset
IM
Grants
NIGMS NIH HHS · R01 GM062281 · United States
NIGMS NIH HHS · GM 062281 · United States
NCI NIH HHS · R01 CA099423 · United States
NCI NIH HHS · CA 06927 · United States
NIGMS NIH HHS · R01 GM049351 · United States
NIGMS NIH HHS · GM 44762 · United States
NCI NIH HHS · CA 99423 · United States
NIGMS NIH HHS · R01 GM044762 · United States
NCI NIH HHS · P01 CA075138 · United States
NCI NIH HHS · P30 CA006927 · United States
NIGMS NIH HHS · GM 49351 · United States
NCI NIH HHS · CA 75138 · United States
External Links
PubMed source DOI: 10.1128/MCB.01639-06 PMC Full Text View journal details
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