3 years ago

CDK9-mediated phosphorylation controls the interaction of TIP60 with the transcriptional machinery

CDK9-mediated phosphorylation controls the interaction of TIP60 with the transcriptional machinery
Lisa Schlicher, Manuela Wissler, Mariam Safavi, Simon Bessler, Martina Weiss, Tilman Brummer, Florian Schubert, Christoph Borner, Cornelius Miething, Prisca Brauns-Schubert, Ulrich Maurer
The acetyltransferase TIP60 is regulated by phosphorylation, and we have previously shown that phosphorylation of TIP60 on S86 by GSK-3 promotes p53-mediated induction of the BCL-2 protein PUMA. TIP60 phosphorylation by GSK-3 requires a priming phosphorylation on S90, and here, we identify CDK9 as a TIP60S90 kinase. We demonstrate that a phosphorylation-deficient mutant, TIP60S90A, exhibits reduced interaction with chromatin, histone 3 and RNA Pol II, while its association with the TIP60 complex subunit EPC1 is not affected. Consistently, we find a diminished association of TIP60S90A with the MYC gene. We show that cells expressing TIP60S90A, but also TIP60S86A, which retains S90 phosphorylation, exhibit reduced histone 4 acetylation and proliferation. Thus, our data indicate that, during transcription, phosphorylation of TIP60 at two sites has different regulatory effects on TIP60, whereby S90 phosphorylation controls association with the transcription machinery, and S86 phosphorylation is regulating TIP60 HAT activity. The phosphorylation of TIP60 by CDK9 provides the priming for GSK-3-mediated phosphorylation of TIP60 and regulates the interaction of TIP60 with chromatin.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.15252/embr.201744311

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