TY - JOUR
T1 - Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60
AU - Sun, Yingli
AU - Jiang, Xiaofeng
AU - Xu, Ye
AU - Ayrapetov, Marina K.
AU - Moreau, Lisa A.
AU - Whetstine, Johnathan R.
AU - Price, Brendan D.
N1 - Funding Information:
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).
PY - 2009
Y1 - 2009
N2 - DNA double-strand break (DSB) repair involves complex interactions between chromatin and repair proteins, including Tip60, a tumour suppressor. Tip60 is an acetyltransferase that acetylates both histones and ATM (ataxia telangiectasia mutated) kinase. Inactivation of Tip60 leads to defective DNA repair and increased cancer risk. 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.
AB - DNA double-strand break (DSB) repair involves complex interactions between chromatin and repair proteins, including Tip60, a tumour suppressor. Tip60 is an acetyltransferase that acetylates both histones and ATM (ataxia telangiectasia mutated) kinase. Inactivation of Tip60 leads to defective DNA repair and increased cancer risk. 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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U2 - 10.1038/ncb1982
DO - 10.1038/ncb1982
M3 - Article
C2 - 19783983
AN - SCOPUS:70449518412
VL - 11
SP - 1376
EP - 1382
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 11
ER -