A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activity

Yun Li, Gary D. Kao, Benjamin A. Garcia, Jeffrey Shabanowitz, Donald F. Hunt, Jun Qin, Caroline Phelan, Mitchell A. Lazar

Research output: Contribution to journalArticlepeer-review

147 Scopus citations

Abstract

Histone deacetylase (HDAC) inhibitors perturb the cell cycle and have great potential as anti-cancer agents, but their mechanism of action is not well established. HDACs classically function as repressors of gene expression, tethered to sequence-specific transcription factors. Here we report that HDAC3 is a critical, transcription-independent regulator of mitosis. HDAC3 forms a complex with A-Kinase-Anchoring Proteins AKAP95 and HA95, which are targeted to mitotic chromosomes. Deacetylation of H3 in mitosis requires AKAP95/HA95 and HDAC3 and provides a hypoacetylated H3 tail that is the preferred substrate for Aurora B kinase. Phosphorylation of H3S10 by Aurora B leads to dissociation of HP1 proteins from methylated H3K9 residues on mitotic heterochromatin. This transcription-independent pathway, involving interdependent changes in histone modification and protein association, is required for normal progression through mitosis and is an unexpected target of HDAC inhibitors, a class of drugs currently in clinical trials for treating cancer.

Original languageEnglish
Pages (from-to)2566-2579
Number of pages14
JournalGenes and Development
Volume20
Issue number18
DOIs
StatePublished - Sep 15 2006

Keywords

  • AKAP
  • Aurora
  • HDAC
  • Histone code
  • Mitosis

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