Fuzzy protein-DNA interactions and beyond: A common theme in transcription?

Gene expression regulation requires both diversity and specificity. How can these two contradictory conditions be reconciled? Dynamic DNA recognition mechanisms lead to heterogeneous bound conformations, which can be shifted by the cellular cues. Here we summarise recent experimental evidence on how fuzzy interactions contribute to chromatin remodelling, regulation of DNA replication and repair and transcription factor binding. We describe how the binding mode continuum between DNA and regulatory factors lead to variable, multisite contact patterns; polyelectrolyte competitions; on-the-fly shape readouts; autoinhibition controlled by post- translational modifications or dynamic oligomerisation mechanisms. Increasing experimental evidence supports the rugged energy landscape of the bound protein-DNA assembly, modulation of which leads to distinct functional outcomes. Recent results suggest the evolutionary conservation of these combinatorial mechanisms with moderate sequence constraints in the malleable transcriptional machinery.