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Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60


DNA double-strand break (DSB) repair involves complex interactions between chromatin and repair proteins, including Tip60, a tumour suppressor1. Tip60 is an acetyltransferase that acetylates both histones2,3,4,5 and ATM (ataxia telangiectasia mutated) kinase6,7. Inactivation of Tip60 leads to defective DNA repair2,3,4 and increased cancer risk8,9,10,11. However, how DNA damage activates the acetyltransferase activity of Tip60 is not known. Here, we show that direct interaction between the chromodomain of Tip60 and histone H3 trimethylated on lysine 9 (H3K9me3) at DSBs activates the acetyltransferase activity of Tip60. Depletion of intracellular H3K9me3 blocks activation of the acetyltransferase activity of Tip60, resulting in defective ATM activation and widespread defects in DSB repair. In addition, the ability of Tip60 to access H3K9me3 is dependent on the DNA damage-induced displacement of HP1β (heterochromatin protein 1β) from H3K9me3. Finally, we demonstrate that the Mre11–Rad50–Nbs1 (MRN) complex targets Tip60 to H3K9me3, and is required to activate the acetyltransferase activity of Tip60. These results reveal a new function for H3K9me3 in coordinating activation of Tip60-dependent DNA repair pathways, and imply that aberrant patterns of histone methylation may contribute to cancer by altering the efficiency of DSB repair.

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Figure 1: The chromodomain of Tip60 is required for its acetyltransferase activity.
Figure 2: MRN is essential for Tip60 activation.
Figure 3: The chromodomain of Tip60 interacts with H3K9me3 in vitro
Figure 4: Demethylation of H3K9 blocks activation of Tip60 acetyltransferase activity.
Figure 5: DNA damage regulates interaction between Tip60 and H3K9me3.

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We thank T. Jenuwein for providing Suv39h1/2 cells, D. Ferguson for providing Rad50-deficient HCT116 cells, and H. Chan, J. Cote, D. Chowdhury and A. D'Andrea for critical discussions and reading of the manuscript. This work was supported by grants from the NCI (CA64585 and CA93602) and the DOD Breast Cancer Program to B.D.P., and by NCI training grants to Y.S. and M.K.A. (T32 CA09078). Y.X. is supported by a U19 Center grant from NIAID (U19AI067751).

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Authors and Affiliations



B.D.P. conceived the research, wrote the paper and carried out data analysis. Y.S. carried out most of the experiments, participated in data analysis, planned experiments and contributed to writing the paper. X.J. carried out the experiments on H2AX, Chk2 and p53 phosphorylation and contributed to data analysis. Y.X. carried out some of the Rad50 experiments and contributed to protocol development. M.K.A. participated in the Rad50 experiments. L.A.M. carried out cytogenetic studies and participated in data analysis. J.R.W. contributed key materials and participated in data analysis. All authors discussed the results and commented on the manuscript.

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Correspondence to Brendan D. Price.

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Sun, Y., Jiang, X., Xu, Y. et al. Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nat Cell Biol 11, 1376–1382 (2009).

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