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Acetylation blocks DNA damage–induced chromatin ADP-ribosylation

Nature Chemical Biology volume 14, pages 837–840 (2018)Cite this article

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Abstract

Recent studies report serine ADP-ribosylation on nucleosomes during the DNA damage response. We unveil histone H3 serine 10 as the primary acceptor residue for chromatin ADP-ribosylation and find that specific histone acetylation marks block this activity. Our results provide a molecular explanation for the well-documented phenomenon of rapid deacetylation at DNA damage sites and support the combinatorial application of PARP and HDAC inhibitors for the treatment of PARP-dependent cancers.

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Fig. 1: DNA-damage-induced H3S10 ADP-ribosylation is blocked by H3K9 acetylation.
Fig. 2: Acetylation of PARP1 regulates its auto- and trans-ADP-ribosylation activities.

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Acknowledgements

We thank current members of the Muir laboratory as well as C.D. Allis for discussions and comments. We also thank the Princeton University Sequencing Core Facility and C. Arrowsmith (University of Toronto) for the SIRT6 expression plasmid. This work was supported by National Institutes of Health (NIH) Grants R37 GM086868, R01 GM107047 and P01 CA196539. G.P.L. and K.L.D. were supported by NIH Research Service Awards (1F32GM110880 and 5F32CA206418, respectively).

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  1. These authors contributed equally: Glen Liszczak, Katharine L. Diehl.

Authors and Affiliations

  1. Department of Chemistry, Princeton University, Princeton, NJ, USA

    Glen Liszczak, Katharine L. Diehl, Geoffrey P. Dann & Tom W. Muir

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  1. Glen Liszczak
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  2. Katharine L. Diehl
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Contributions

G.L. and K.L.D. performed all experiments. G.P.D. assisted with DNA barcode sorting following high-throughput DNA sequencing. G.L., K.L.D., and T.W.M. analyzed all data and wrote the manuscript.

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Correspondence to Tom W. Muir.

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The authors declare no competing interests.

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Supplementary information

Supplementary Text and Figures

Supplementary Table 1, Supplementary Figures 1–26

Reporting Summary

Supplementary Dataset 1

Mononucleosome library binding and ADP-ribosylation activity measurements for PARP1–HPF1 and PARP2–HPF1.

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Liszczak, G., Diehl, K.L., Dann, G.P. et al. Acetylation blocks DNA damage–induced chromatin ADP-ribosylation. Nat Chem Biol 14, 837–840 (2018). https://doi.org/10.1038/s41589-018-0097-1

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