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

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Abstract

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.

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Acknowledgements

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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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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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) doi:10.1038/nature03714

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