2. Academic Validation
  3. CDK9-mediated phosphorylation controls the interaction of TIP60 with the transcriptional machinery

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

  • EMBO Rep. 2018 Feb;19(2):244-256. doi: 10.15252/embr.201744311.
Prisca Brauns-Schubert 1 2 3 4,  Florian Schubert 1 2 3 4,  Manuela Wissler 1,  Martina Weiss 1,  Lisa Schlicher 1 2 3 4,  Simon Bessler 4,  Mariam Safavi 4,  Cornelius Miething 5 6 7,  Christoph Borner 1 2 3,  Tilman Brummer 1 2 3 6 7,  Ulrich Maurer 8 2 3
Affiliations

Affiliations

  • 1 Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
  • 2 Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.
  • 3 BIOSS, Centre for Biological Signaling Studies, Freiburg, Germany.
  • 4 Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 5 Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
  • 6 German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.
  • 7 German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 8 Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany ulrich.maurer@mol-med.uni-freiburg.de.
PMID: 29335245 DOI: 10.15252/embr.201744311
Abstract

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.

Keywords

CDK9; TIP60; apoptosis; chromatin; transcription.

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