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

Abstract

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