Role of an ING1 growth regulator in transcriptional activation and targeted histone acetylation by the NuA4 complex.
The yeast NuA4 complex is a histone H4 and H2A acetyltransferase involved in transcription regulation and essential for cell cycle progression. We identify here a novel subunit of the complex, Yng2p, a plant homeodomain (PHD)-finger protein homologous to human p33/ING1, which has tumor suppressor activity and is essential for p53 function. Mass spectrometry, immunoblotting, and immunoprecipitation experiments confirm the stable stoichiometric association of this protein with purified NuA4. Yeast cells harboring a deletion of the YNG2 gene show severe growth phenotype and have gene-specific transcription defects. NuA4 complex purified from the mutant strain is low in abundance and shows weak histone acetyltransferase activity. We demonstrate conservation of function by the requirement of Yng2p for p53 to function as a transcriptional activator in yeast. Accordingly, p53 interacts with NuA4 in vitro and in vivo, an interaction reminiscent of the p53-ING1 physical link in human cells. The growth defect of Delta yng2 cells can be rescued by the N-terminal part of the protein, lacking the PHD-finger. While Yng2 PHD-finger is not required for p53 interaction, it is necessary for full expression of the p53-responsive gene and other NuA4 target genes. Transcriptional activation by p53 in vivo is associated with targeted NuA4-dependent histone H4 hyperacetylation, while histone H3 acetylation levels remain unchanged. These results emphasize the essential role of the NuA4 complex in the control of cell proliferation through gene-specific transcription regulation. They also suggest that regulation of mammalian cell proliferation by p53-dependent transcriptional activation functions through recruitment of an ING1-containing histone acetyltransferase complex.
Nourani
A
A
Laval University Cancer Research Center, Hôtel-Dieu de Québec, Quebec City, Quebec G1R 2J6, Canada.
Doyon
Y
Y
Utley
R T
RT
Allard
S
S
Lane
W S
WS
Côté
J
J
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004268:DNA-Binding Proteins; D016147:Genes, Tumor Suppressor; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010940:Plant Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011506:Proteins; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010940:Plant Proteins; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C438844:Yng2p protein, plant; D000123:Acetyltransferases; D051548:Histone Acetyltransferases