Regulation of Tip60S90 phosphorylation by CDK9: implications for a role in the regulation of transcription

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

Tip60 is an acetyltransferase with roles in transcriptional regulation, apoptosis, DNA damage sensing and repair. Tip60 was shown to be a haplo-insufficient tumor suppressor, as the absence of a single allele promoted the formation of lymphoma. We could previously show that Tip60 is subject to phosphorylation by GSK-3, and is thereby regulated by the PI3K pathway. We demonstrated that the transcriptional induction of the pro-apoptotic BH3 protein PUMA and apoptosis by p53 upon DNA damage requires GSK-3.  Specifically, GSK-3 mediated the phosphorylation of serine 86 of Tip60. We further showed that this phosphorylation promotes acetylation of lysine 120 (K129) of p53 by Tip60, which had been shown before to be required for PUMA induction and apoptosis by p53.

Phosphorylation of Tip60 on S86 by GSK-3 requires a pre-existing phosphorylation on serine S90, which is mediated by a priming kinase. We have now identified CDK9 as a Tip60S90 kinase. Moreover, addressing the role of the Tip60S90 phosphorylation, we have found that an Tip60^S90A mutant exhibits largely reduced association with chromatin.