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.

中文翻译：

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应激反应基因ATF3调节组蛋白乙酰转移酶Tip60。

Tat相互作用蛋白60（Tip60）是一种MYST组蛋白乙酰基转移酶，可催化主要DNA损伤激酶共济失调毛细血管扩张症（ATM）的乙酰化，从而触发维持基因毒性损害的基因组稳定性所需的细胞信号传导。Tip60活性是通过翻译后修饰来调节的，这些修饰会改变其稳定性以及与底物的相互作用。在这里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去泛素化来提高Tip60的稳定性。所以，累积的DNA损伤和细胞对辐射的敏感性增加证明了ATF3表达的降低导致Tip60表达的降低和ATM信号的抑制。因此，我们的发现揭示了常见的压力调节因子在调节Tip60功能方面的未知功能。