Cui Hongmei, Guo Mingxiong, Xu Dong, Ding Zhi-Chun, Zhou Gang, Ding Han-Fei, Zhang Junran, Tang Yi, Yan Chunhong
1] GRU Cancer Center, Georgia Regents University, 1120 15th Street, Augusta, Georgia 30912, USA [2] Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA.
Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA.
Nat Commun. 2015 Apr 13;6:6752. doi: 10.1038/ncomms7752.
Tat-interactive protein 60 (Tip60) is a MYST histone acetyltransferase that catalyses acetylation of the major DNA damage kinase Ataxia telangiectasia mutated (ATM), thereby triggering cellular signalling required for the maintenance of genomic stability on genotoxic insults. The Tip60 activity is modulated by post-translational modifications that alter its stability and its interactions with substrates. Here we report that activating transcription factor 3 (ATF3), a common stress mediator and a p53 activator, is a regulator of Tip60. ATF3 directly binds Tip60 at a region adjacent to the catalytic domain to promote the protein acetyltransferase activity. Moreover, the ATF3-Tip60 interaction increases the Tip60 stability by promoting USP7-mediated deubiquitination of Tip60. Consequently, knockdown of ATF3 expression leads to decreased Tip60 expression and suppression of ATM signalling as evidenced by accumulated DNA lesions and increased cell sensitivity to irradiation. Our findings thus reveal a previously unknown function of a common stress mediator in regulating Tip60 function.
Tat 相互作用蛋白 60（Tip60）是一种 MYST 组蛋白乙酰转移酶，可催化主要的 DNA 损伤激酶共济失调毛细血管扩张突变蛋白（ATM）的乙酰化，从而触发在基因毒性损伤时维持基因组稳定性所需的细胞信号传导。Tip60 的活性受到翻译后修饰的调节，这些修饰会改变其稳定性及其与底物的相互作用。在此，我们报告激活转录因子 3（ATF3），一种常见的应激介质和 p53 激活剂，是 Tip60 的调节剂。ATF3 在与催化结构域相邻的区域直接结合 Tip60，以促进蛋白质乙酰转移酶活性。此外，ATF3 - Tip60 相互作用通过促进 USP7 介导的 Tip60 去泛素化增加 Tip60 的稳定性。因此，ATF3 表达的敲低导致 Tip60 表达降低和 ATM 信号传导的抑制，这表现为 DNA 损伤积累和细胞对辐射的敏感性增加。我们的研究结果因此揭示了一种常见应激介质在调节 Tip60 功能方面以前未知的功能。
