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The p53-SET Interplays Reveal A New Mode of Acetylation-dependent Regulation #MMPMID27626385
Wang D; Kon N; Lasso G; Jiang L; Leng W; Zhu WG; Qin J; Honig B; Gu W
Nature 2016[Oct]; 538 (7623): 118-22 PMID27626385show ga
Although lysine acetylation is now recognized as a general protein modification for both histones and non-histone proteins1-3, 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 acetylation4. Yet the precise role of the CTD acetylation remains elusive. Lysine acetylation often creates binding sites for bromodomain-containing ?reader? proteins5,6; 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.
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Nature 2016 ; 538 (7623): 118-22
