Regulation of NuA4 histone acetyltransferase activity in transcription and DNA repair by phosphorylation of histone H4

Mol Cell Biol. 2005 Sep;25(18):8179-90. doi: 10.1128/MCB.25.18.8179-8190.2005.

Abstract

The NuA4 complex is a histone H4/H2A acetyltransferase involved in transcription and DNA repair. While histone acetylation is important in many processes, it has become increasingly clear that additional histone modifications also play a crucial interrelated role. To understand how NuA4 action is regulated, we tested various H4 tail peptides harboring known modifications in HAT assays. While dimethylation at arginine 3 (R3M) had little effect on NuA4 activity, phosphorylation of serine 1 (S1P) strongly decreased the ability of the complex to acetylate H4 peptides. However, R3M in combination with S1P alleviates the repression of NuA4 activity. Chromatin from cells treated with DNA damage-inducing agents shows an increase in phosphorylation of serine 1 and a concomitant decrease in H4 acetylation. We found that casein kinase 2 phosphorylates histone H4 and associates with the Rpd3 deacetylase complex, demonstrating a physical connection between phosphorylation of serine 1 and unacetylated H4 tails. Chromatin immunoprecipitation experiments also link local phosphorylation of H4 with its deacetylation, during both transcription and DNA repair. Time course chromatin immunoprecipitation data support a model in which histone H4 phosphorylation occurs after NuA4 action during double-strand break repair at the step of chromatin restoration and deacetylation. These findings demonstrate that H4 phospho-serine 1 regulates chromatin acetylation by the NuA4 complex and that this process is important for normal gene expression and DNA repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Acetyltransferases / metabolism*
  • Amino Acid Sequence
  • Casein Kinase II / metabolism
  • Chromatin / metabolism
  • DNA Damage
  • DNA Repair*
  • Drug Resistance, Fungal / genetics
  • Histone Acetyltransferases
  • Histone Deacetylases / metabolism
  • Histones / genetics
  • Histones / metabolism*
  • Hydroxyurea / pharmacology
  • Mesylates / pharmacology
  • Molecular Sequence Data
  • Mutation
  • Peptides / genetics
  • Peptides / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Repressor Proteins / metabolism
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Serine / metabolism
  • Transcription Factors / metabolism
  • Transcription, Genetic*

Substances

  • Chromatin
  • Histones
  • Mesylates
  • Peptides
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • methanesulfonic acid
  • Serine
  • Acetyltransferases
  • Histone Acetyltransferases
  • NuA4 protein, S cerevisiae
  • Casein Kinase II
  • Protein Serine-Threonine Kinases
  • RPD3 protein, S cerevisiae
  • Histone Deacetylases
  • Hydroxyurea