The role of GSK-3 mediated phosphorylation of the acetyltransferase Tip60 for apoptosis and the DNA damage response

Dr. Ulrich Maurer and Dr. Tilman Brummer (Institute of Molecular Medicine, University of Freiburg)

The Tip60 acetyltransferase has multiple roles in diverse cellular processes, such as transcriptional control and apoptosis induction, the DNA damage response and DNA repair. Tip60 contributes to these processes by acetylation of histones, but also non-histone protein targets, including p53.

We characterized Tip60 as a bona fide substrate of glycogen synthase kinase-3 (GSK-3), showing that serine-86 of Tip60 is phosphorylated by GSK-3, which is suppressed by PI3K signalling. Tip60S86 phosphorylation facilitated the induction of the pro-apoptotic BH3 protein PUMA and apoptosis upon p53 activation by DNA damage, by acetylation of p53 at Lysine-120 as well as by acetylation of H4 on the puma promoter. As we found that Tip60S90 phosphorylation is required for S86 phosphorylation, we will explore which kinase mediates this priming phosphorylation. Importantly, Tip60 is essential for DNA damage signalling and DNA repair, and we will investigate the role of its phosphorylation on S86 and S90 in this context.