Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode.
Although lysine acetylation is now recognized as a general protein modification for both histones and non-histone proteins, the mechanisms of acetylation-mediated actions are not completely understood. Acetylation of the C-terminal domain (CTD) of p53 (also known as TP53) was an early example of non-histone protein acetylation and its precise role remains unclear. Lysine acetylation often creates binding sites for bromodomain-containing 'reader' proteins. Here we use a proteomic screen to identify the oncoprotein SET as a major cellular factor whose binding with p53 is dependent on CTD acetylation status. SET profoundly inhibits p53 transcriptional activity in unstressed cells, but SET-mediated repression is abolished by stress-induced acetylation of p53 CTD. Moreover, loss of the interaction with SET activates p53, resulting in tumour regression in mouse xenograft models. Notably, the acidic domain of SET acts as a 'reader' for the unacetylated CTD of p53 and this mechanism of acetylation-dependent regulation is widespread in nature. For example, acetylation of p53 also modulates its interactions with similar acidic domains found in other p53 regulators including VPRBP (also known as DCAF1), DAXX and PELP1 (refs. 7, 8, 9), and computational analysis of the proteome has identified numerous proteins with the potential to serve as acidic domain readers and lysine-rich ligands. Unlike bromodomain readers, which preferentially bind the acetylated forms of their cognate ligands, the acidic domain readers specifically recognize the unacetylated forms of their ligands. Finally, the acetylation-dependent regulation of p53 was further validated in vivo by using a knock-in mouse model expressing an acetylation-mimicking form of p53. These results reveal that acidic-domain-containing factors act as a class of acetylation-dependent regulators by targeting p53 and, potentially, other proteins.
Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY 10032, USA.
Donglai
D
Wang
Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY 10032, USA.
Ning
N
Kon
Department of Biochemistry and Molecular Biophysics and Systems Biology, Center for Computational Biology and Bioinformatics, Howard Hughes Medical Institute, Columbia University, 1130 Nicholas Ave, New York, NY 10032, USA.
Gorka
G
Lasso
Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY 10032, USA.
Le
L
Jiang
State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China.
Wenchuan
W
Leng
Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518060, China.
Wei-Guo
WG
Zhu
State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China.|Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Jun
J
Qin
Department of Biochemistry and Molecular Biophysics and Systems Biology, Center for Computational Biology and Bioinformatics, Howard Hughes Medical Institute, Columbia University, 1130 Nicholas Ave, New York, NY 10032, USA.
Barry
B
Honig
Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY 10032, USA.
Wei
W
Gu
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D005260:Female; D056488:Histone Chaperones / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D000072417:Protein Domains; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D006657:Histones; D008024:Ligands; D012097:Repressor Proteins; C513473:SET protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors