The homeodomain drives favorable DNA binding energetics of prostate cancer target ONECUT2

• DOI: 10.1101/2023.06.13.544830
• Publication Date: 2023-06-14T10:55:11Z
• Authors: Avradip Chatterjee; Brad Gallent; Madhusudhanarao K...; Chen Qian; Matthew R. Harter; Michael R. Freeman; Ramachandran Murali
• Keywords: Energetics

The ONECUT transcription factors feature a CUT and homeodomain, evolutionarily conserved elements that bind DNA cooperatively, but the process remains mechanistically enigmatic. Using an integrative binding analysis of ONECUT2, driver aggressive prostate cancer, we show homeodomain energetically stabilizes ONECUT2-DNA complex through allosteric modulation CUT. Further, base-interactions in both are necessary for favorable thermodynamics. We have identified novel arginine pair unique to family can adapt sequence variations. Base interactions general, including by this pair, critical optimal cancer model. These findings provide fundamental insights into CUT-homeodomain proteins with potential therapeutic implications.