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CBP/p300-mediated acetylation of histone H3 on lysine 56

A Corrigendum to this article was published on 27 August 2009

Abstract

Acetylation within the globular core domain of histone H3 on lysine 56 (H3K56) has recently been shown to have a critical role in packaging DNA into chromatin following DNA replication and repair in budding yeast1,2. However, the function or occurrence of this specific histone mark has not been studied in multicellular eukaryotes, mainly because the Rtt109 enzyme that is known to mediate acetylation of H3K56 (H3K56ac) is fungal-specific3,4. Here we demonstrate that the histone acetyl transferase CBP (also known as Nejire) in flies and CBP and p300 (Ep300) in humans acetylate H3K56, whereas Drosophila Sir2 and human SIRT1 and SIRT2 deacetylate H3K56ac. The histone chaperones ASF1A in humans and Asf1 in Drosophila are required for acetylation of H3K56 in vivo, whereas the histone chaperone CAF-1 (chromatin assembly factor 1) in humans and Caf1 in Drosophila are required for the incorporation of histones bearing this mark into chromatin. We show that, in response to DNA damage, histones bearing acetylated K56 are assembled into chromatin in Drosophila and human cells, forming foci that colocalize with sites of DNA repair. Furthermore, acetylation of H3K56 is increased in multiple types of cancer, correlating with increased levels of ASF1A in these tumours. Our identification of multiple proteins regulating the levels of H3K56 acetylation in metazoans will allow future studies of this critical and unique histone modification that couples chromatin assembly to DNA synthesis, cell proliferation and cancer.

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Figure 1: Drosophila Asf1 promotes H3K56 acetylation whereas Caf1 deposits H3K56ac into chromatin.
Figure 2: Drosophila CBP acetylates H3K56 whereas Sir2 deacetylates H3K56ac in vivo.
Figure 3: Human CBP and p300 acetylate H3K56 whereas SIRT1 and SIRT2 deacetylate H3K56ac.
Figure 4: Asf1a drives K56 acetylation in human cells and tumours.

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Acknowledgements

We thank J. Kadonaga for Drosophila embryos and the Sir2 antibody, A. Mazo for the CBP antisera, and E. Nigg for ASF1A/B antisera. We thank C. Wike and the UC microscope core, and the UCCC flow cytometry core for assistance. This work was supported by funding from the National Institutes of Health (grants GM64475 and CA95641) to J.K.T.

Author Contributions C.D. performed all the experiments, and devised some of the experiments. K.H. performed all the mass spectrometry analyses, M.S.L. performed all the pathology and immunohistochemistry analyses, J.K.T. and C.D. wrote the manuscript and J.K.T. guided the research.

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Correspondence to Jessica K. Tyler.

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Das, C., Lucia, M., Hansen, K. et al. CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature 459, 113–117 (2009). https://doi.org/10.1038/nature07861

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