Target site localization by site-specific, DNA-binding proteins

Bacterial genomes contain over a million base pairs of DNA, and the human genome contains over a billion base pairs, yet specific locations in all this DNA must be reached and recognized in a timely manner by just a handful of molecules of any given site-specific, DNA-binding protein. How proteins rapidly search the entire genome to find a specific site has been the subject of intense discussion for decades but remains mysterious. In a recent issue of PNAS, a new article by Gowers et al. (1) provided a clear experimental distinction between two different but similar appearing search mechanisms.

Work on this problem of DNA target site location began in earnest with a startling report by Riggs and colleagues (2), who showed that the Escherichia coli lac repressor protein bound to a specific target site in vitro 1,000 times faster than had been imagined possible. Subsequent studies from other groups confirmed this conclusion and extended the results to many other protein-DNA systems. Basic explanations of these results and detailed theoretical models were developed by Berg and von Hippel and their colleagues (3-5) and have since been extended to consider searching over protein-DNA complexes, such as chromatin (6), and to define the optimal search strategy (7-9).

Three distinct search mechanisms, known collectively as “facilitated diffusion,” are now recognized to contribute importantly to a protein's ability to search along nonspecific DNA to find a specific target site. In the “sliding” mechanism, a protein diffuses along the length of the DNA without dissociating. The reduced dimensionality of the sliding process accelerates encounters over short distances, whereas the random walk nature of sliding (forward and backward steps are equally probable) makes this mode of searching very inefficient for long distances. In the “intersegment transfer” mechanism, a protein having two …