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The homeodomain regulates stable DNA binding of prostate cancer target ONECUT2

Author

Listed:
  • Avradip Chatterjee

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Brad Gallent

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Madhusudhanarao Katiki

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Chen Qian

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Matthew R. Harter

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Steve Silletti

    (University of California San Diego)

  • Elizabeth A. Komives

    (University of California San Diego)

  • Michael R. Freeman

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Ramachandran Murali

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

Abstract

The CUT and homeodomain are ubiquitous DNA binding elements often tandemly arranged in multiple transcription factor families. However, how the CUT and homeodomain work concertedly to bind DNA remains unknown. Using ONECUT2, a driver and therapeutic target of advanced prostate cancer, we show that while the CUT initiates DNA binding, the homeodomain thermodynamically stabilizes the ONECUT2-DNA complex through allosteric modulation of CUT. We identify an arginine pair in the ONECUT family homeodomain that can adapt to DNA sequence variations. Base interactions by this ONECUT family-specific arginine pair as well as the evolutionarily conserved residues are critical for optimal DNA binding and ONECUT2 transcriptional activity in a prostate cancer model. The evolutionarily conserved base interactions additionally determine the ONECUT2-DNA binding energetics. These findings provide insights into the cooperative DNA binding by CUT-homeodomain proteins.

Suggested Citation

  • Avradip Chatterjee & Brad Gallent & Madhusudhanarao Katiki & Chen Qian & Matthew R. Harter & Steve Silletti & Elizabeth A. Komives & Michael R. Freeman & Ramachandran Murali, 2024. "The homeodomain regulates stable DNA binding of prostate cancer target ONECUT2," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53159-8
    DOI: 10.1038/s41467-024-53159-8
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    References listed on IDEAS

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    1. Peter D. Kwong & Richard Wyatt & James Robinson & Raymond W. Sweet & Joseph Sodroski & Wayne A. Hendrickson, 1998. "Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody," Nature, Nature, vol. 393(6686), pages 648-659, June.
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