Published online 3 June 2004
Nucleic Acids Research, 2004, Vol. 32, No. 10 3040-3052
How do site-specific DNA-binding proteins find their targets?
Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK and 1 Department of Physics, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7059, USA
*To whom correspondence should be addressed. Tel: +44 117 928 7429; Fax: +44 117 928 8274; Email: s.halford{at}bristol.ac.uk
Correspondence may also be addressed to John F. Marko. Tel: +1 312 996 6064; Fax: +1 312 996 9016; Email: jmarko{at}uic.edu
Received March 31, 2004; Revised and Accepted May 6, 2004
Essentially all the biological functions of DNA depend on site-specific DNA-binding proteins finding their targets, and therefore ‘searching’ through megabases of non-target DNA. In this article, we review current understanding of how this sequence searching is done. We review how simple diffusion through solution may be unable to account for the rapid rates of association observed in experiments on some model systems, primarily the Lac repressor. We then present a simplified version of the ‘facilitated diffusion’ model of Berg, Winter and von Hippel, showing how non-specific DNA–protein interactions may account for accelerated targeting, by permitting the protein to sample many binding sites per DNA encounter. We discuss the 1-dimensional ‘sliding’ motion of protein along non-specific DNA, often proposed to be the mechanism of this multiple site sampling, and we discuss the role of short-range diffusive ‘hopping’ motions. We then derive the optimal range of sliding for a few physical situations, including simple models of chromosomes in vivo, showing that a sliding range of 
100 bp before dissociation optimizes targeting in vivo. Going beyond first-order binding kinetics, we discuss how processivity, the interaction of a protein with two or more targets on the same DNA, can reveal the extent of sliding and we review recent experiments studying processivity using the restriction enzyme EcoRV. Finally, we discuss how single molecule techniques might be used to study the dynamics of DNA site-specific targeting of proteins.
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