Protein-DNA binding in the absence of specific base-pair recognition

Until now, it has been reasonably assumed that specific base-pair recognition is the only mechanism controlling the specificity of transcription factor (TF)-DNA binding. Contrary to this assumption, here we show that nonspecific DNA sequences possessing certain repeat symmetries, when present outside of specific TF binding sites (TFBSs), statistically control TF -DNA binding preferences. We used highthroughput protein-DNAbinding assays to measure the binding levels and free energies of binding for several humanTFs to tens of thousands of short DNA sequences with varying repeat symmetries. Based on statisticalmechanicsmodeling, weidentifyanewprotein-DNAbinding mechanism induced by DNA sequence symmetry in the absence of specific base-pair recognition, and experimentally demonstrate that this mechanism indeed governs protein-DNA binding preferences.