TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition

• Published in: Nature communications Vol. 14; no. 1; pp. 5362 - 12
• Main Authors: Xu, Longxia, Xuan, Hongwen, He, Wei, Zhang, Liang, Huang, Mengying, Li, Kuai, Wen, Hong, Xu, Han, Shi, Xiaobing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 38/15; 38/22; 38/23; 38/39; 38/70; 38/88; 38/91; 49/47; 631/337/100/2285; 631/337/458/1275; Acetylation; Cancer; CREB-binding protein; Cyclic AMP response element-binding protein; Histone acetyltransferase; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histones; Humanities and Social Sciences; Humans; Inhibition, Psychological; multidisciplinary; Protein interaction; Proteins; Science; Science (multidisciplinary); Substrates; Transcription factors; Transcription Factors - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41245-2

The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds to E1A and various transcription factors. Here we show that TAZ2 has a HAT autoinhibitory function. Truncating p300/CBP at TAZ2 leads to hyperactive HAT and elevated histone H3K27 and H3K18 acetylation in cells. Mechanistically, TAZ2 cooperates with other HAT neighboring domains to maintain the HAT active site in a ‘closed’ state. Truncating TAZ2 or binding of transcription factors to TAZ2 induces a conformational change that ‘opens’ the active site for substrate acetylation. Importantly, genetic mutations that lead to p300/CBP TAZ2 truncations are found in human cancers, and cells with TAZ2 truncations are vulnerable to histone deacetylase inhibitors. Our study reveals a function of the TAZ2 domain in HAT autoinhibitory regulation and provides a potential therapeutic strategy for the treatment of cancers harboring p300/CBP TAZ2 truncations. The E1A binding protein p300 and its close paralogue CREB-binding protein are transcriptional coactivators with intrinsic histone acetyltransferase activity. Here, the authors show that the TAZ2 domain of p300 has a HAT autoinhibitory function that is relieved upon binding of transcription factors.