Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode

Donglai Wang, Ning Kon, Gorka Lasso, Le Jiang, Wenchuan Leng, Wei Guo Zhu, Jun Qin, Barry Honig, Wei Gu

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)118-122
Number of pages5
JournalNature
Volume538
Issue number7623
DOIs
StatePublished - Sep 14 2016
Externally publishedYes

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Acetylation
Lysine
Proteins
Ligands
Histone Code
Oncogene Proteins
Proteome
Heterografts
Proteomics
Binding Sites

ASJC Scopus subject areas

  • General

Cite this

Wang, D., Kon, N., Lasso, G., Jiang, L., Leng, W., Zhu, W. G., ... Gu, W. (2016). Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. Nature, 538(7623), 118-122. https://doi.org/10.1038/nature19759

Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. / Wang, Donglai; Kon, Ning; Lasso, Gorka; Jiang, Le; Leng, Wenchuan; Zhu, Wei Guo; Qin, Jun; Honig, Barry; Gu, Wei.

In: Nature, Vol. 538, No. 7623, 14.09.2016, p. 118-122.

Research output: Contribution to journalArticle

Wang, D, Kon, N, Lasso, G, Jiang, L, Leng, W, Zhu, WG, Qin, J, Honig, B & Gu, W 2016, 'Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode', Nature, vol. 538, no. 7623, pp. 118-122. https://doi.org/10.1038/nature19759
Wang, Donglai ; Kon, Ning ; Lasso, Gorka ; Jiang, Le ; Leng, Wenchuan ; Zhu, Wei Guo ; Qin, Jun ; Honig, Barry ; Gu, Wei. / Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. In: Nature. 2016 ; Vol. 538, No. 7623. pp. 118-122.
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