Investigation of the regulation of the histone acetyltransferase Tip60 by phosphorylation

Abstract: In eukaryotic cells, DNA is packed into chromatin. To facilitate gene transcription, histone acetyltransferases (HATs) acetylate the lysine residues at the N-terminus of core histones, thereby mediating chromatin relaxation. This process is reversed by histone deacetylases (HDACs), which usually repress gene transcription.
The acetyltransferase Tip60 has diverse roles in transcriptional regulation, in apoptosis, in DNA damage sensing and in DNA double strand break repair.
Interestingly, Tip60 was shown to be a haplo-insufficient tumour suppressor, as the absence of a single allele promoted the formation of a c-Myc-driven lymphoma.
Hence, it is obvious that an enzyme, with so many different functions in cellular homoeostasis, has to be tightly controlled.
We could previously show that Tip60 activity in transcriptional induction of the pro-apoptotic BH3-only protein Puma requires GSK-3 mediated phosphorylation of Tip60 S86. Phosphorylation of Tip60 S86 by GSK3 requires phosphorylation on S90, which is mediated by a priming kinase.
In this study, CDK9, which is the catalytic subunit of the general transcription elongation factor P-TEFb, was identified as a kinase mediating phosphorylation of Tip60 S90 in vitro and in vivo. Further, the phosphorylation of Tip60 S90 was found to promote association of Tip60 with chromatin, Histone 3 and with RNA Pol II, while the association of Tip60 with the Tip60 complex subunit EPC1 was independent of the phosphorylation on S90. Thus, CDK9 was found to regulate the recruitment of Tip60 to chromatin. BRD4 regulates CDK9 activity in induction of transcriptional elongation. Consistent with that, BRD4 was found to influence recruitment of Tip60 to chromatin,
just like CDK9. Importantly, in vivo, Tip60 HAT activity and cellular growth were dependent on the phosphorylations of S86 and S90, possibly indicating a broader role of these phosphorylations in transcriptional control.
In summary, a model is proposed, in which Tip60 recruitment to chromatin and association of Tip60 with H3 are regulated by CDK9, which is downstream of BRD4. Bound to chromatin, Tip60 has to be phosphorylated additionally on S86 by GSK3 to gain full HAT activity

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2017

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2017
• Creator: Brauns-Schubert, Priska
• Contributor: Maurer, Ulrich ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Further information

• DOI: 10.6094/UNIFR/12772
• URN: urn:nbn:de:bsz:25-freidok-127720
• Rights: Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:47 PM CET