Regulation of NuA4 histone acetyltransferase activity in transcription and DNA repair by phosphorylation of histone H4.
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.
Utley
Rhea T
RT
Laval University Cancer Research Center, Hôtel-Dieu de Québec (CHUQ), 9 McMahon Street, Quebec City, QC, Canada G1R 2J6.
Lacoste
Nicolas
N
Jobin-Robitaille
Olivier
O
Allard
Stéphane
S
Côté
Jacques
J
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000595:Amino Acid Sequence; D047390:Casein Kinase II / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D025141:Drug Resistance, Fungal / Q000235:genetics; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006918:Hydroxyurea / Q000494:pharmacology; D008698:Mesylates / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D002843:Chromatin; D006657:Histones; D008698:Mesylates; D010455:Peptides; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C045880:methanesulfonic acid; D012694:Serine; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C504740:NuA4 protein, S cerevisiae; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; C071665:RPD3 protein, S cerevisiae; D006655:Histone Deacetylases; D006918:Hydroxyurea