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A role for cell-cycle-regulated histone H3 lysine 56 acetylation in the DNA damage response


DNA breaks are extremely harmful lesions that need to be repaired efficiently throughout the genome. However, the packaging of DNA into nucleosomes is a significant barrier to DNA repair, and the mechanisms of repair in the context of chromatin are poorly understood1. Here we show that lysine 56 (K56) acetylation is an abundant modification of newly synthesized histone H3 molecules that are incorporated into chromosomes during S phase. Defects in the acetylation of K56 in histone H3 result in sensitivity to genotoxic agents that cause DNA strand breaks during replication. In the absence of DNA damage, the acetylation of histone H3 K56 largely disappears in G2. In contrast, cells with DNA breaks maintain high levels of acetylation, and the persistence of the modification is dependent on DNA damage checkpoint proteins. We suggest that the acetylation of histone H3 K56 creates a favourable chromatin environment for DNA repair and that a key component of the DNA damage response is to preserve this acetylation.

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Figure 1: Newly synthesized histone H3 is acetylated at K56.
Figure 2: Histone H3 K56 contributes to survival of camptothecin (CPT) and bleomycin-induced DNA breaks.
Figure 3: Rad9-dependent retention of histone H3 K56 acetylation at sites of CPT-induced DNA breaks.
Figure 4: The positive charge of histone H3 K56 is important for histone–DNA interactions at the entry and exit points from the nucleosome core particle.


  1. 1

    Peterson, C. L. & Côté, J. Cellular machineries for chromosomal DNA repair. Genes Dev. 18, 602–616 (2004)

    CAS  Article  Google Scholar 

  2. 2

    Kuo, M. H. et al. Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines. Nature 383, 269–272 (1996)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Sklenar, A. R. & Parthun, M. R. Characterization of yeast histone H3-specific type B histone acetyltransferases identifies an ADA2-independent Gcn5p activity. BMC Biochem. 5, 1–12 (2004)

    Article  Google Scholar 

  4. 4

    Ye, J. et al. Histone H4 lysine 91 acetylation: A core domain modification associated with chromatin assembly. Mol. Cell 18, 123–130 (2005)

    CAS  Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

    Gunjan, A. & Verreault, A. A Rad53 kinase-dependent surveillance mechanism that regulates histone protein levels in S. cerevisiae. Cell 115, 537–549 (2003)

    CAS  Article  Google Scholar 

  7. 7

    Downs, J. A., Lowndes, N. F. & Jackson, S. P. A role for Saccharomyces cerevisiae histone H2A in DNA repair. Nature 408, 1001–1004 (2000)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Redon, C. et al. Yeast histone 2A serine 129 is essential for the efficient repair of checkpoint-blind DNA damage. EMBO Rep. 4, 678–684 (2003)

    CAS  Article  Google Scholar 

  9. 9

    Pilch, D. R. et al. Characteristics of γ-H2AX foci at DNA double-strand break sites. Biochem. Cell Biol. 81, 123–129 (2003)

    CAS  Article  Google Scholar 

  10. 10

    Bird, A. W. et al. Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature 419, 411–415 (2002)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Haber, J. E. Partners and pathways: repairing a double-strand break. Trends Genet. 16, 259–264 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Pommier, Y. et al. Repair of and checkpoint response to topoisomerase I-mediated DNA damage. Mutat. Res. 532, 173–203 (2003)

    CAS  Article  Google Scholar 

  13. 13

    Hsiang, Y. H., Lihou, M. G. & Liu, L. F. Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res. 49, 5077–5082 (1989)

    CAS  PubMed  Google Scholar 

  14. 14

    Nitiss, J. L. & Wang, J. C. Mechanisms of cell killing by drugs that trap covalent complexes between DNA topoisomerases and DNA. Mol. Pharmacol. 50, 1095–1102 (1996)

    CAS  PubMed  Google Scholar 

  15. 15

    Tercero, J. A., Longhese, M. P. & Diffley, J. F. X. A central role for DNA replication forks in checkpoint activation and response. Mol. Cell 11, 1323–1326 (2003)

    CAS  Article  Google Scholar 

  16. 16

    Davey, C. A., Sargent, D. F., Luger, K., Maeder, A. W. & Richmond, T. J. Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 Å resolution. J. Mol. Biol. 319, 1097–1113 (2002)

    CAS  Article  Google Scholar 

  17. 17

    Norton, V. G., Imai, B. S., Yau, P. & Bradbury, E. M. Histone acetylation reduces nucleosome core particle linking number change. Cell 57, 449–457 (1989)

    CAS  Article  Google Scholar 

  18. 18

    Wechser, M. A., Kladde, M. P., Alfieri, J. A. & Peterson, C. L. Effects of Sin- versions of histone H4 on yeast chromatin structure and function. EMBO J. 16, 2086–2095 (1997)

    CAS  Article  Google Scholar 

  19. 19

    Sogo, J. M., Stahl, H., Koller, T. & Knippers, R. Structure of replicating simian virus 40 minichromosomes. The replication fork, core histone segregation and terminal structures. J. Mol. Biol. 189, 189–204 (1986)

    CAS  Article  Google Scholar 

  20. 20

    Downs, J. A. et al. Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. Mol. Cell 16, 979–990 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Kushnirov, V. V. Rapid and reliable protein extraction from yeast. Yeast 16, 857–860 (2000)

    CAS  Article  Google Scholar 

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We thank W. Bonner, M. Christman, J. Diffley, L. Drury, P. Fitzjohn, H. Nash, A. Kristjuhan, D. Lyon, C. Redon, D. Stillman, J. Svejstrup and S. Tanaka for reagents, and A. Castillo and A. Gunjan for critical reading of the manuscript. This work was funded by Cancer Research UK and the International Association for Cancer Research. H.M. was supported by postdoctoral fellowships from the NAITO Foundation and Cancer Research UK.

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Correspondence to Alain Verreault.

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Masumoto, H., Hawke, D., Kobayashi, R. et al. A role for cell-cycle-regulated histone H3 lysine 56 acetylation in the DNA damage response. Nature 436, 294–298 (2005).

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