How to Scan DNA using Promiscuous Recognition and No Sliding Clamp: A Model for Pioneer Transcription Factors

DNA scanning proteins slide on the DNA assisted by a clamping interface and uniquely recognize their cognate sequence motif. The transcription factors that control cell fate in eukaryotes must forgo these elements to gain access to both naked DNA and chromatin, so whether or how they scan DNA is unknown. Here we use single-molecule techniques to investigate DNA scanning by the Engrailed homeodomain (enHD) as paradigm of promiscuous recognition and open DNA interaction. We find that enHD scans DNA as fast and extensively as conventional scanners and 10,000,000 fold faster than expected for a continuous promiscuous slide. Our results indicate that such supercharged scanning involves stochastic alternants between local sequence sweeps of ∼85 bp and very rapid deployments to locations ∼500 bp afar. The scanning mechanism of enHD reveals a strategy perfectly suited for the highly complex environments of eukaryotic cells that might be generally used by pioneer transcription factors. Teaser Eukaryotic transcription factors can efficiently scan DNA using a rather special mechanism based on promiscuous recognition. ### Competing Interest Statement The authors have declared no competing interest.