Tip60 acetylation of histone H3K4 temporally controls chromosome passenger complex localization

Ewa Niedzialkowska, Limin Liu, Cem Kuscu, Zachary Mayo, Wladek Minor, Brian D. Strahl, Mazhar Adli, P. Todd Stukenberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The Chromosome Passenger Complex (CPC) generates chromosome autonomous signals that regulate mitotic events critical for genome stability. Tip60 is a lysine acetyltransferase that is a tumor suppressor and is targeted for proteasomal degradation by oncogenic papilloma viruses. Mitotic regulation requires the localization of the CPC to inner centromeres, which is driven by the Haspin kinase phosphorylating histone H3 on threonine 3 (H3T3ph). Here we describe how Tip60 acetylates histone H3 at lysine 4 (H3K4ac) to block both the H3T3ph writer and the reader to ensure that this mitotic signaling cannot begin before prophase. Specifically, H3K4ac inhibits Haspin phosphorylation of H3T3 and prevents binding of the Survivin subunit to H3T3ph. Tip60 acetylates H3K4 during S/G2 at centromeres. Inhibition of Tip60 allows the CPC to bind centromeres in G2 cells, and targeting of Tip60 to centromeres prevents CPC localization in mitosis. The H3K4ac mark is removed in prophase by HDAC3 to initiate the CPC localization cascade. Together, our results suggest that Tip60 and HDAC3 temporally control H3K4 acetylation to precisely time the targeting of the CPC to inner centromeres.

Original languageEnglish (US)
Article numberbr15
JournalMolecular biology of the cell
Volume33
Issue number9
DOIs
StatePublished - Aug 1 2022

Funding

The work described here was supported by NIH Grants No. GM118798 and No. GM124042 to P.T.S., No. GM126900 to B.D.S., No. GM053163 to W.M.; E.N. was supported by a grant from the Schiff foundation. The structural data shown in this report used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Use of the SBC 19-ID sector was supported by the Structural Biology Center (SBC). Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant No. 085P1000817).

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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