Abstract
Tat-interactive protein 60 (Tip60) is a MYST histone acetyltransferase that catalyzes acetylation of the major DNA damage kinase ATM, thereby triggering cellular signaling required for the maintenance of genomic stability upon genotoxic insults. The Tip60 activity is modulated by posttranslational 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 signaling 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.
Highlights
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
We found that the FLAG antibody could precipitate activating transcription factor 3 (ATF3) along with the FLAG-tagged Tip[60] protein (Fig. 1e)—a result demonstrating that the endogenous Tip[60] and ATF3 proteins could interact
The results show that ATF3 interacted with Tip[60] after DNA damage (Fig. 1f, lanes 6–8, and Supplementary Fig. 1, lanes 5 and 6)
Summary
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. Tip[60] appears to determine the cell fate on genotoxic stress by acetylating the tumour suppressor p53 at lysine 120, thereby selectively promoting pro-apoptotic gene (for example, PUMA) expression[7,8] It is essential for the cell to tightly regulate Tip[60] expression and its histone acetyltransferase (HAT) activity in order to maintain genomic integrity and evade from malignant transformation in the face of genotoxic insults. Consistent with these results, knockdown of ATF3 expression leads to decreased Tip[60] expression and impaired ATM activation on IR These findings unveil a novel, pivotal role that ATF3 plays in the regulation of Tip[60] activity and subsequent signalling essential for the maintenance of genomic stability on genotoxic stress
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