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Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1

Author

Listed:
  • Xueyong Xu

    (Institute of Molecular and Cell Biology)

  • Yinghui Li

    (Institute of Molecular and Cell Biology)

  • Sakshibeedu R. Bharath

    (Institute of Molecular and Cell Biology)

  • Mert Burak Ozturk

    (Institute of Molecular and Cell Biology
    National University of Singapore)

  • Matthew W. Bowler

    (Grenoble Outstation
    Univ. Grenoble Alpes-EMBL-CNRS)

  • Bryan Zong Lin Loo

    (Institute of Molecular and Cell Biology)

  • Vinay Tergaonkar

    (Institute of Molecular and Cell Biology
    National University of Singapore
    University of South Australia and SA Pathology)

  • Haiwei Song

    (Institute of Molecular and Cell Biology
    National University of Singapore)

Abstract

Transcriptional factors ETS1/2 and p52 synergize downstream of non-canonical NF-κB signaling to drive reactivation of the −146C>T mutant TERT promoter in multiple cancer types, but the mechanism underlying this cooperativity remains unknown. Here we report the crystal structure of a ternary p52/ETS1/−146C>T TERT promoter complex. While p52 needs to associate with consensus κB sites on the DNA to function during non-canonical NF-κB signaling, we show that p52 can activate the −146C>T TERT promoter without binding DNA. Instead, p52 interacts with ETS1 to form a heterotetramer, counteracting autoinhibition of ETS1. Analogous to observations with the GABPA/GABPB heterotetramer, the native flanking ETS motifs are required for sustained activation of the −146C>T TERT promoter by the p52/ETS1 heterotetramer. These observations provide a unifying mechanism for transcriptional activation by GABP and ETS1, and suggest that genome-wide targets of non-canonical NF-κB signaling are not limited to those driven by consensus κB sequences.

Suggested Citation

  • Xueyong Xu & Yinghui Li & Sakshibeedu R. Bharath & Mert Burak Ozturk & Matthew W. Bowler & Bryan Zong Lin Loo & Vinay Tergaonkar & Haiwei Song, 2018. "Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05644-0
    DOI: 10.1038/s41467-018-05644-0
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    Cited by:

    1. Nicholas Sim & Jean-Michel Carter & Kamalakshi Deka & Benita Kiat Tee Tan & Yirong Sim & Suet-Mien Tan & Yinghui Li, 2024. "TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Daniel A. Ang & Jean-Michel Carter & Kamalakshi Deka & Joel H. L. Tan & Jianbiao Zhou & Qingfeng Chen & Wee Joo Chng & Nathan Harmston & Yinghui Li, 2024. "Aberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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