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Slide and Find
Transcription factors rapidly find their specific binding sites on chromosomal DNA. It has been proposed that searching is facilitated by complementing three-dimensional diffusion with one-dimensional diffusion along DNA. Such sliding on DNA has been observed in vitro, but whether and how far transcription factors slide along chromosomes in vivo is unclear. Hammar et al. (p. 1595) used single-molecule imaging to demonstrate that the lac repressor slides into its chromosomal operators in living cells. The average sliding distance was about 45 base pairs, and the repressor frequently slid over its operator before binding.
Transcription factors (TFs) are proteins that regulate the expression of genes by binding sequence-specific sites on the chromosome. It has been proposed that to find these sites fast and accurately, TFs combine one-dimensional (1D) sliding on DNA with 3D diffusion in the cytoplasm. This facilitated diffusion mechanism has been demonstrated in vitro, but it has not been shown experimentally to be exploited in living cells. We have developed a single-molecule assay that allows us to investigate the sliding process in living bacteria. Here we show that the lac repressor slides 45 ± 10 base pairs on chromosomal DNA and that sliding can be obstructed by other DNA-bound proteins near the operator. Furthermore, the repressor frequently (>90%) slides over its natural lacO1 operator several times before binding. This suggests a trade-off between rapid search on nonspecific sequences and fast binding at the specific sequence.