组蛋白乙酰转移酶p300/CBP由若干保守结构域组成，其中TAZ2结构域作为蛋白质-蛋白质相互作用结构域，与E1A和各种转录因子结合。本研究表明TAZ2具有组蛋白乙酰转移酶（HAT）的自抑制功能。在TAZ2截短的p300/CBP中，细胞中的HAT活性过高，并且组蛋白H3K27和H3K18的乙酰化水平升高。在机制上，TAZ2与其他靠近的HAT结构域合作，将HAT活性位点维持在“闭合”状态。截短TAZ2或转录因子与TAZ2结合会引发构象变化，使活性位点“打开”，从而使底物得以乙酰化。值得注意的是，导致p30 /CBP TAZ2截短的基因突变在人类癌症中广泛存在，而TAZ2截短的细胞对组蛋白去乙酰化酶抑制剂更加敏感。我们的研究揭示了TAZ2结构域在HAT自抑制调节中的功能，并提供了一种潜在治疗策略，用于治疗携带p300/CBP TAZ2截短的癌症。© 2023. Springer Nature Limited.

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.© 2023. Springer Nature Limited.