Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Biol Chem. 2010 Apr 9;285(15):11458-64. doi: 10.1074/jbc.M109.087585. Epub 2010 Jan 25.
The histone acetyltransferase TIP60, a frequent target of monoallelic loss in human carcinomas, can acetylate many substrates, including histones and p53, and thus promote apoptosis following UV radiation. Here we showed that TIP60 is autoacetylated in response to UV damage, which is critically important for TIP60 activation. Mechanistically we demonstrated that TIP60 autoacetylation leads to the dissociation of TIP60 oligomer and enhances its interaction with substrates. Moreover, we identified SIRT1 that specifically deacetylates TIP60 and negatively regulates TIP60 activity in vivo. Taken together, our data reveal TIP60 autoacetylation as a key step in the control of its histone acetyltransferase activity and function in response to DNA damage.
组蛋白乙酰转移酶 TIP60 是人类癌组织中单等位基因缺失的常见靶点，它可以乙酰化许多底物，包括组蛋白和 p53，从而促进紫外线辐射后的细胞凋亡。在这里，我们发现 TIP60 可以自身乙酰化来响应紫外线损伤，这对 TIP60 的激活至关重要。从机制上讲，我们证明 TIP60 的自身乙酰化导致 TIP60 寡聚体的解离，并增强其与底物的相互作用。此外，我们鉴定了 SIRT1，它可以特异性去乙酰化 TIP60，并在体内负调控 TIP60 的活性。总之，我们的数据揭示了 TIP60 的自身乙酰化是控制其组蛋白乙酰转移酶活性和功能以响应 DNA 损伤的关键步骤。
