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Molecular and Cellular Biology, September 2005, p. 8179-8190, Vol. 25, No. 18
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.18.8179-8190.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulation of NuA4 Histone Acetyltransferase Activity in Transcription and DNA Repair by Phosphorylation of Histone H4

Rhea T. Utley,{dagger} Nicolas Lacoste,{dagger} Olivier Jobin-Robitaille, Stéphane Allard, and Jacques Côté*

Laval University Cancer Research Center, Hôtel-Dieu de Québec (CHUQ), Quebec City, QC, Canada G1R 2J6

Received 15 April 2005/ Returned for modification 6 May 2005/ Accepted 21 June 2005

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.

* Corresponding author. Mailing address: Laval University Cancer Research Center, Hôtel-Dieu de Québec (CHUQ), 9 McMahon Street, Quebec City, QC, Canada G1R 2J6. Phone: (418) 525-4444, ext. 15545. Fax: (418) 691-5439. E-mail: Jacques.Cote{at}crhdq.ulaval.ca.

{dagger} These authors contributed equally to this work

Molecular and Cellular Biology, September 2005, p. 8179-8190, Vol. 25, No. 18
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.18.8179-8190.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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