SET is an acetylation-dependent negative regulator of p53 that binds its unacetylated CTD.
Major finding: SET is an acetylation-dependent negative regulator of p53 that binds its unacetylated CTD.
Concept: SET suppresses p53 activity to promote tumor growth in vitro and in vivo.
Impact: Acidic domain proteins are acetylation-dependent regulators of p53, and potentially other proteins.
The C-terminal domain (CTD) of p53 can be acetylated, but the exact function of this post-translational modification is not well understood. To identify p53 binding proteins dependent on CTD acetylation, Wang, Kon, and colleagues generated unacetylated and fully acetylated p53 CTD peptides and analyzed their binding partners by mass spectrometry, which identified SET as a specific binding partner of unacetylated p53. The acidic domain of SET bound directly to the CTD of p53, and expression of CREB-binding protein (CBP), which acetylates the p53 CTD, prevented SET binding to wild-type but not acetylation-deficient p53, further indicating that SET binds specifically to the unacetylated p53 CTD. Under unstressed conditions, SET acted as a transcriptional corepressor of p53; it bound DNA only when in complex with p53 and reduced p53 transcriptional activity and expression of p53 target genes. However, DNA damage induced CTD acetylation, disrupted the p53–SET interaction, and enhanced p53 transcriptional activity. In vivo, SET depletion reduced the growth of tumor xenografts in a p53-dependent manner, as SET depletion had no effect on tumor growth in p53-deficient tumors. Of note, SET also regulates other proteins with lysine-rich domains similar to the p53 CTD including KU70, FOXO1, and histone H3, and, similar to p53, acetylation blocked binding of the SET acidic domain to these proteins. These findings suggest a widespread function of the SET acidic domain as a “converse reader” that specifically recognizes unacetylated proteins. Moreover, mouse embryonic fibroblasts expressing an acetylation-mimicking p53 mutant exhibited a severe proliferation defect, increased senescence, and enhanced p53 activity. Collectively, these findings demonstrate the essential role of the p53–SET interaction in vivo and uncover a mechanism of acetylation-dependent p53 regulation that may extend to other proteins with lysine-rich domains.
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