Protein-DNA Binding in the Absence of Consensus Binding Motif

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. In our study 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 high-throughput protein-DNA binding assays to measure the binding levels for several human TFs to tens of thousands of short DNA sequences with varying repeat symmetries. Based on statistical mechanics modeling, we identify a new protein-DNA binding mechanism induced by DNA sequence symmetry in the absence of consensus binding motif, and experimentally demonstrate that this mechanism indeed highly affects protein-DNA binding preferences.