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

Author

Listed:
  • Longxia Xu

    (Van Andel Institute)

  • Hongwen Xuan

    (Van Andel Institute)

  • Wei He

    (The University of Texas MD Anderson Cancer Center)

  • Liang Zhang

    (The University of Texas MD Anderson Cancer Center)

  • Mengying Huang

    (Van Andel Institute)

  • Kuai Li

    (Van Andel Institute)

  • Hong Wen

    (Van Andel Institute)

  • Han Xu

    (The University of Texas MD Anderson Cancer Center)

  • Xiaobing Shi

    (Van Andel Institute)

Abstract

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.

Suggested Citation

  • Longxia Xu & Hongwen Xuan & Wei He & Liang Zhang & Mengying Huang & Kuai Li & Hong Wen & Han Xu & Xiaobing Shi, 2023. "TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41245-2
    DOI: 10.1038/s41467-023-41245-2
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