Abstract 5364: ATF3 contributes to the DNA damage response by regulating the histone acetyltransferase Tip60

Abstract

Abstract Activating transcription factor 3 (ATF3) is a common stress mediator, and its expression is rapidly induced upon DNA damage. Although we have demonstrated that ATF3 can activate the tumor suppressor p53 and regulate expression of p53 target genes, the consequences of ATF3 induction by DNA damage remain elusive. Tat-interactive protein 60 (Tip60) belongs to the MYST family of histone acetyltransferase, and plays important roles in regulating chromatin remodeling, transcription, and the DNA damage response. While Tip60-mediated p53 acetylation promotes pro-apoptotic gene expression, Tip60 can also catalyze acetylation of ATM resulting in increased ATM kinase activity thereby mobilizing DNA repair machinery. Here we report that ATF3 can directly bind Tip60 and regulates its function in the DNA damage response. ATF3 binds Tip60 via its leucine zipper domain, and can increase Tip60 stability by blocking its ubiquitination. This effect is achieved through ATF3 binding to Tip60 as an ATF3 mutant devoid of Tip60 binding fails to block Tip60 ubiquitination and stabilize Tip60. Consistent with these results, knockdown of ATF3 expression decreases the level of Tip60 protein, but not its mRNA. Interestingly, ATM phosphorylation, a marker for ATM activation, is significantly suppressed in ATF3 knockdown cells. Therefore, we identified that ATF3 as a novel regulator of Tip60 in the DNA damage response. Our results suggest that, consistent with its tumor suppressor role, ATF3 may contribute to the DNA damage response by activating ATM signaling. Citation Format: Hongmei Cui. ATF3 contributes to the DNA damage response by regulating the histone acetyltransferase Tip60. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5364. doi:10.1158/1538-7445.AM2014-5364