The homeodomain regulates stable DNA binding of prostate cancer target ONECUT2

Avradip Chatterjee, Brad Gallent, Madhusudhanarao Katiki, Chen Qian, Matthew R. Harter, Steve Silletti, Elizabeth A. Komives, Michael R. Freeman () and Ramachandran Murali ()
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Avradip Chatterjee: Cedars-Sinai Medical Center
Brad Gallent: Cedars-Sinai Medical Center
Madhusudhanarao Katiki: Cedars-Sinai Medical Center
Chen Qian: Cedars-Sinai Medical Center
Matthew R. Harter: 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
Ramachandran Murali: Cedars-Sinai Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53159-8

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