Sun Yingli, Jiang Xiaofeng, Xu Ye, Ayrapetov Marina K, Moreau Lisa A, Whetstine Johnathan R, Price Brendan D
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA.
Nat Cell Biol. 2009 Nov;11(11):1376-82. doi: 10.1038/ncb1982. Epub 2009 Sep 27.
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 HP1beta (heterochromatin protein 1beta) 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.
DNA双链断裂（DSB）修复涉及染色质与修复蛋白之间的复杂相互作用，其中包括肿瘤抑制因子Tip60。Tip60是一种乙酰转移酶，可使组蛋白和共济失调毛细血管扩张症突变激酶（ATM）乙酰化。Tip60失活会导致DNA修复缺陷并增加患癌风险。然而，DNA损伤如何激活Tip60的乙酰转移酶活性尚不清楚。在此，我们表明Tip60的色域与DSB处赖氨酸9三甲基化的组蛋白H3（H3K9me3）之间的直接相互作用激活了Tip60的乙酰转移酶活性。细胞内H3K9me3的缺失会阻断Tip60乙酰转移酶活性的激活，导致ATM激活缺陷和DSB修复广泛缺陷。此外，Tip60接近H3K9me3的能力取决于DNA损伤诱导的异染色质蛋白1β（HP1β）从H3K9me3的位移。最后，我们证明Mre11-Rad50-Nbs1（MRN）复合物将Tip60靶向H3K9me3，并激活Tip60的乙酰转移酶活性。这些结果揭示了H3K9me3在协调Tip60依赖性DNA修复途径激活中的新功能，并暗示组蛋白甲基化异常模式可能通过改变DSB修复效率而导致癌症。
