Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres

Nature Structural & Molecular Biology volume 17, pages 1218–1225 (2010)Cite this article

Subjects

Abstract

During replicative aging of primary cells morphological transformations occur, the expression pattern is altered and chromatin changes globally. Here we show that chronic damage signals, probably caused by telomere processing, affect expression of histones and lead to their depletion. We investigated the abundance and cell cycle expression of histones and histone chaperones and found defects in histone biosynthesis during replicative aging. Simultaneously, epigenetic marks were redistributed across the phases of the cell cycle and the DNA damage response (DDR) machinery was activated. The age-dependent reprogramming affected telomeric chromatin itself, which was progressively destabilized, leading to a boost of the telomere-associated DDR with each successive cell cycle. We propose a mechanism in which changes in the structural and epigenetic integrity of telomeres affect core histones and their chaperones, enforcing a self-perpetuating pathway of global epigenetic changes that ultimately leads to senescence.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Altered histone biosynthesis and redistribution of epigenetic marks upon chronic damage and cellular aging.
Figure 2: Cell cycle distribution of histone modifications in early- and late-passage cells.
Figure 3: DNA damage accumulation and DDR activation upon cellular aging.
Figure 4: Telomerase expression resets late-passage cells to early-passage cells.
Figure 5: Cellular aging leads to an altered chromatin landscape of human telomeres.

Similar content being viewed by others

References

  1. Kaygun, H. & Marzluff, W.F. Translation termination is involved in histone mRNA degradation when DNA replication is inhibited. Mol. Cell. Biol. 25, 6879–6888 (2005).

    Article  CAS  Google Scholar 

  2. Su, C. et al. DNA damage induces downregulation of histone gene expression through the G1 checkpoint pathway. EMBO J. 23, 1133–1143 (2004).

    Article  CAS  Google Scholar 

  3. Groth, A. et al. Human Asf1 regulates the flow of S phase histones during replicational stress. Mol. Cell 17, 301–311 (2005).

    Article  CAS  Google Scholar 

  4. Hoek, M. & Stillman, B. Chromatin assembly factor 1 is essential and couples chromatin assembly to DNA replication in vivo. Proc. Natl. Acad. Sci. USA 100, 12183–12188 (2003).

    Article  CAS  Google Scholar 

  5. Das, C., Lucia, M.S., Hansen, K.C. & Tyler, J.K. CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature 459, 113–117 (2009).

    Article  CAS  Google Scholar 

  6. Tjeertes, J.V., Miller, K.M. & Jackson, S.P. Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells. EMBO J. 28, 1878–1889 (2009).

    Article  CAS  Google Scholar 

  7. Bunz, F. et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282, 1497–1501 (1998).

    Article  CAS  Google Scholar 

  8. Wang, Z.F., Whitfield, M.L., Ingledue, T.C. III, Dominski, Z. & Marzluff, W.F. The protein that binds the 3′ end of histone mRNA: a novel RNA-binding protein required for histone pre-mRNA processing. Genes Dev. 10, 3028–3040 (1996).

    Article  CAS  Google Scholar 

  9. Whitfield, M.L. et al. Stem-loop binding protein, the protein that binds the 3′ end of histone mRNA, is cell cycle regulated by both translational and posttranslational mechanisms. Mol. Cell. Biol. 20, 4188–4198 (2000).

    Article  CAS  Google Scholar 

  10. Zhang, Z., Shibahara, K. & Stillman, B. PCNA connects DNA replication to epigenetic inheritance in yeast. Nature 408, 221–225 (2000).

    Article  CAS  Google Scholar 

  11. Gérard, A. et al. The replication kinase Cdc7-Dbf4 promotes the interaction of the p150 subunit of chromatin assembly factor 1 with proliferating cell nuclear antigen. EMBO Rep. 7, 817–823 (2006).

    PubMed  PubMed Central  Google Scholar 

  12. Juan, G., Hernando, E. & Cordon-Cardo, C. Separation of live cells in different phases of the cell cycle for gene expression analysis. Cytometry 49, 170–175 (2002).

    Article  Google Scholar 

  13. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  Google Scholar 

  14. Bernstein, B.E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005).

    Article  CAS  Google Scholar 

  15. Fischle, W. et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev. 17, 1870–1881 (2003).

    Article  CAS  Google Scholar 

  16. Francis, N.J., Follmer, N.E., Simon, M.D., Aghia, G. & Butler, J.D. Polycomb proteins remain bound to chromatin and DNA during DNA replication in vitro. Cell 137, 110–122 (2009).

    Article  CAS  Google Scholar 

  17. Goldstein, S. Replicative senescence: the human fibroblast comes of age. Science 249, 1129–1133 (1990).

    Article  CAS  Google Scholar 

  18. Chen, E.S. et al. Cell cycle control of centromeric repeat transcription and heterochromatin assembly. Nature 451, 734–737 (2008).

    Article  CAS  Google Scholar 

  19. Kloc, A., Zaratiegui, M., Nora, E. & Martienssen, R. RNA interference guides histone modification during the S phase of chromosomal replication. Curr. Biol. 18, 490–495 (2008).

    Article  CAS  Google Scholar 

  20. Peters, A.H. et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol. Cell 12, 1577–1589 (2003).

    Article  CAS  Google Scholar 

  21. Imai, S., Armstrong, C.M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).

    Article  CAS  Google Scholar 

  22. Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008).

    Article  CAS  Google Scholar 

  23. Chen, C.C. et al. Acetylated lysine 56 on histone H3 drives chromatin assembly after repair and signals for the completion of repair. Cell 134, 231–243 (2008).

    Article  CAS  Google Scholar 

  24. Hayashi, R. et al. Transcriptional regulation of human chromatin assembly factor ASF1. DNA Cell Biol. 26, 91–99 (2007).

    Article  CAS  Google Scholar 

  25. Jasencakova, Z. et al. Replication stress interferes with histone recycling and predeposition marking of new histones. Mol. Cell 37, 736–743 (2010).

    Article  CAS  Google Scholar 

  26. Harper, J.W. & Elledge, S.J. The DNA damage response: ten years after. Mol. Cell 28, 739–745 (2007).

    Article  CAS  Google Scholar 

  27. Petrini, J.H. & Stracker, T.H. The cellular response to DNA double-strand breaks: defining the sensors and mediators. Trends Cell Biol. 13, 458–462 (2003).

    Article  CAS  Google Scholar 

  28. Stracker, T.H., Couto, S.S., Cordon-Cardo, C., Matos, T. & Petrini, J.H. Chk2 suppresses the oncogenic potential of DNA replication-associated DNA damage. Mol. Cell 31, 21–32 (2008).

    Article  CAS  Google Scholar 

  29. Scaffidi, P. & Misteli, T. Lamin A-dependent nuclear defects in human aging. Science 312, 1059–1063 (2006).

    Article  CAS  Google Scholar 

  30. Stewart, S.A. et al. Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc. Natl. Acad. Sci. USA 99, 12606–12611 (2002).

    Article  CAS  Google Scholar 

  31. Blasco, M.A. The epigenetic regulation of mammalian telomeres. Nat. Rev. Genet. 8, 299–309 (2007).

    Article  CAS  Google Scholar 

  32. Grunstein, M. Yeast heterochromatin: Regulation of its assembly and inheritance by histones. Cell 93, 325–328 (1998).

    Article  CAS  Google Scholar 

  33. Bianchi, A. & Shore, D. Early replication of short telomeres in budding yeast. Cell 128, 1051–1062 (2007).

    Article  CAS  Google Scholar 

  34. Meeks-Wagner, D. & Hartwell, L.H. Normal stoichiometry of histone dimer sets is necessary for high fidelity of mitotic chromosome transmission. Cell 44, 43–52 (1986).

    Article  CAS  Google Scholar 

  35. Steger, D.J. & Workman, J.L. Transcriptional analysis of purified histone acetyltransferase complexes. Methods 19, 410–416 (1999).

    Article  CAS  Google Scholar 

  36. Harris, M.E. et al. Regulation of histone mRNA in the unperturbed cell cycle: evidence suggesting control at two posttranscriptional steps. Mol. Cell. Biol. 11, 2416–2424 (1991).

    Article  CAS  Google Scholar 

  37. Dominski, Z., Zheng, L.X., Sanchez, R. & Marzluff, W.F. Stem-loop binding protein facilitates 3′-end formation by stabilizing U7 snRNP binding to histone pre-mRNA. Mol. Cell. Biol. 19, 3561–3570 (1999).

    Article  CAS  Google Scholar 

  38. Groth, A. et al. Regulation of replication fork progression through histone supply and demand. Science 318, 1928–1931 (2007).

    Article  CAS  Google Scholar 

  39. Dang, W. et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802–807 (2009).

    Article  CAS  Google Scholar 

  40. Michishita, E. et al. Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle 8, 2664–2666 (2009).

    Article  CAS  Google Scholar 

  41. Recht, J. et al. Histone chaperone Asf1 is required for histone H3 lysine 56 acetylation, a modification associated with S phase in mitosis and meiosis. Proc. Natl. Acad. Sci. USA 103, 6988–6993 (2006).

    Article  CAS  Google Scholar 

  42. Li, Q. et al. Acetylation of histone H3 lysine 56 regulates replication-coupled nucleosome assembly. Cell 134, 244–255 (2008).

    Article  CAS  Google Scholar 

  43. Maas, N.L., Miller, K.M., DeFazio, L.G. & Toczyski, D.P. Cell cycle and checkpoint regulation of histone H3 K56 acetylation by Hst3 and Hst4. Mol. Cell 23, 109–119 (2006).

    Article  CAS  Google Scholar 

  44. Schotta, G. et al. A silencing pathway to induce H3–K9 and H4–K20 trimethylation at constitutive heterochromatin. Genes Dev. 18, 1251–1262 (2004).

    Article  CAS  Google Scholar 

  45. Feng, Q. et al. Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr. Biol. 12, 1052–1058 (2002).

    Article  CAS  Google Scholar 

  46. van Leeuwen, F., Gafken, P.R. & Gottschling, D.E. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745–756 (2002).

    Article  CAS  Google Scholar 

  47. Nishioka, K. et al. PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol. Cell 9, 1201–1213 (2002).

    Article  CAS  Google Scholar 

  48. Altaf, M. et al. Interplay of chromatin modifiers on a short basic patch of histone H4 tail defines the boundary of telomeric heterochromatin. Mol. Cell 28, 1002–1014 (2007).

    Article  CAS  Google Scholar 

  49. d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    Article  CAS  Google Scholar 

  50. Denchi, E.L. & de Lange, T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448, 1068–1071 (2007).

    Article  CAS  Google Scholar 

  51. Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003).

    Article  CAS  Google Scholar 

  52. Dimitrova, N., Chen, Y.C., Spector, D.L. & de Lange, T. 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature 456, 524–528 (2008).

    Article  CAS  Google Scholar 

  53. Crabbe, L., Verdun, R.E., Haggblom, C.I. & Karlseder, J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306, 1951–1953 (2004).

    Article  CAS  Google Scholar 

  54. Fodor, B.D. et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562 (2006).

    Article  CAS  Google Scholar 

  55. Verdun, R.E. & Karlseder, J. The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Cell 127, 709–720 (2006).

    Article  CAS  Google Scholar 

  56. Azuara, V. Profiling of DNA replication timing in unsynchronized cell populations. Nat. Protoc. 1, 2171–2177 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Almouzni (Institut Curie) for sharing antibodies to Asf1a and Asf1b and for helpful discussions. We are grateful to T. Jenuwein (Max Planck Institute of Immunobiology) for the gift of the H3K9, H3K27 and H4K20 series of antibodies, T. Hunter (Salk Institute) for cyclin antibodies, T. de Lange (The Rockefeller University) for advice on chronic damage protocols, J. Jaffe (Broad Institute) and S. Carr (Broad Institute) for access to the Broad Proteomics Platform, expert advice and helpful discussion. We also thank D. Chambers (Salk Institute) and J. Barrie (Salk Institute) for technical assistance with flow cytometry. We are grateful to members of the Karlseder lab for critical discussion of the manuscript. R.J.O'S. is supported by the George E. Hewitt Foundation for Medical Research, S.K. is supported by a postdoctoral fellowship of the Ernst Schering Research Foundation and the European Union, and J.K. acknowledges support by the US National Institutes of Health (RO1 GM06525 and RO1 AG025837).

Author information

Author notes

  1. Stefan Kubicek

    Present address: Present address: Research Center for Molecular Medicine (CeMM), Vienna, Austria.,

Authors and Affiliations

  1. Molecular and Cellular Biology Department, The Salk Institute for Biological Studies, La Jolla, California, USA

    Roderick J O'Sullivan & Jan Karlseder

  2. The Broad Institute, Cambridge, Massachusetts, USA

    Stefan Kubicek & Stuart L Schreiber

  3. Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts, USA

    Stuart L Schreiber

  4. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA

    Stuart L Schreiber

Authors
  1. Roderick J O'Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stefan Kubicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stuart L Schreiber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Karlseder
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.J.O'S. designed and carried out experiments and wrote the manuscript, S.K. did the MS analysis, S.L.S. provided advice and access to the MS facilities, and J.K. designed experiments and wrote the manuscript.

Corresponding author

Correspondence to Jan Karlseder.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Table 1 (PDF 3315 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

O'Sullivan, R., Kubicek, S., Schreiber, S. et al. Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nat Struct Mol Biol 17, 1218–1225 (2010). https://doi.org/10.1038/nsmb.1897

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.1897

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing