Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis.
Upon DNA damage and other types of stress, p53 induces either cell-cycle arrest or apoptosis depending on the cellular context. However, the molecular mechanisms that govern the choice between cell-cycle arrest and apoptosis are not well understood. Here, we show that Tip60 is required for both cell growth arrest and apoptosis mediated by p53 and also induces its acetylation specifically at lysine 120 (K120) within the DNA-binding domain. Interestingly, this modification is crucial for p53-dependent apoptosis but is dispensable for its mediated growth arrest. K120 is a recurrent site for p53 mutation in human cancer, and the corresponding acetylation-defective tumor mutant (K120R) abrogates p53-mediated apoptosis, but not growth arrest. Thus, our study demonstrates that Tip60-dependent acetylation of p53 at K120 modulates the decision between cell-cycle arrest and apoptosis, and it reveals that the DNA-binding core domain is an important target for p53 regulation by posttranslational modifications.
Tang
Yi
Y
Institute for Cancer Genetics, Surgeons, Columbia University, 1150 St. Nicholas Ave, New York, New York 10032, USA.
Luo
Jianyuan
J
Zhang
Wenzhu
W
Gu
Wei
W
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000502:physiology; D000099224:p300-CBP-Associated Factor
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051548:Histone Acetyltransferases; D000074443:Lysine Acetyltransferase 5; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C438378:BBC3 protein, human; C493956:CDKN1A protein, human; C098489:KAT5 protein, human; C497206:MDM2 protein, human