SIRT1 Regulates Autoacetylation and Histone Acetyltransferase Activity of TIP60

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. 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.