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The p53-SET Interplays Reveal A New Mode of Acetylation-dependent Regulation

Although lysine acetylation is now recognized as a general protein modification for both histones and non-histone proteins(1-3), the mechanisms of acetylation mediated actions are not completely understood. Acetylation of the C-terminal domain (CTD) of p53 was the first example for non-histone prote...

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Detalles Bibliográficos
Autores principales: Wang, Donglai, Kon, Ning, Lasso, Gorka, Jiang, Le, Leng, Wenchuan, Zhu, Wei-Guo, Qin, Jun, Honig, Barry, Gu, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333498/
https://www.ncbi.nlm.nih.gov/pubmed/27626385
http://dx.doi.org/10.1038/nature19759
Descripción
Sumario:Although lysine acetylation is now recognized as a general protein modification for both histones and non-histone proteins(1-3), the mechanisms of acetylation mediated actions are not completely understood. Acetylation of the C-terminal domain (CTD) of p53 was the first example for non-histone protein acetylation(4). Yet the precise role of the CTD acetylation remains elusive. Lysine acetylation often creates binding sites for bromodomain-containing “reader” proteins(5,6); surprisingly, in a proteomic screen, we identified SET as a major cellular factor whose binding with p53 is totally dependent on the CTD acetylation status. SET profoundly inhibits p53 transcriptional activity in unstressed cells but SET-mediated repression is completely abolished by stress-induced p53 CTD acetylation. Moreover, loss of the interaction with SET activates p53, resulting in tumor regression in mouse xenograft models. Notably, the acidic domain of SET acts as a “reader” for unacetylated CTD of p53 and this mechanism of acetylation-dependent regulation is widespread in nature. For example, p53 acetylation also modulates its interactions with similar acidic domains found in other p53 regulators including VPRBP, DAXX and PELP1 (refs. 7-9), and computational analysis of the proteome identified numerous proteins with the potential to serve as the 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 knockin mouse model expressing an acetylation-mimicking form of p53. These results reveal that the acidic domain-containing factors act as a new class of acetylation-dependent regulators by targeting p53 and potentially, beyond.