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DNA Bends to Bind

Sean Henahan

A new discovery about how cells regulate protein synthesis helps explain the complex interactions between proteins and DNA and may have far reaching implications for future biotechnology research.

In order to inhibit gene expression, proteins need to bind to specific DNA target sites, which are often located in stretches of non-specific DNA. The mechanism for recognition and discrimination between non-specific and specific sites has remained a mystery. Researchers at the Institute of Molecular Biology, University of Oregon, used a new imaging technique called scanning force microscopy (SFM) to visualize DNA and protein complexes in the process of binding..

SFM fills a need for quantitative analysis of DNA not possible with X-ray crystallography. SFM provides a topographic image of a molecular surface by scanning a surface underneath a tip modified with an electron beam. Deflections sensed by the tip can be amplified and recorded, providing a quantitative topographic map of the surface.

Previous studies have shown that recognition of a specific target site is often accompanied by DNA "bending." However, the significance of this bending has not been understood. SFM studies revealed crucial differences in DNA bending induced by protein binding to non-specific and specific sites.

The researchers studied the binding of Cro, a protein that regulates genes in bacterial viruses, to DNA containing non-specific and specific binding sites. Cro binds loosely to DNA at non-specific sites, and travels along the chain until it recognizes a specific target site, where it binds very tightly. The SFM studies revealed an increase in the DNA bending angle where the protein is bound to a specific site.

The investigators hypothesize that Cro first binds loosely and non-specifically to the DNA, then produces a "bending wave" as it travels along the strand. The DNA is more easily bent at a specific target site, allowing the protein to "check" for specific contacts. The DNA bending seen in the presence of Cro has several important implications. The observation helps explain the dynamics of one-dimensional diffusion along the DNA, its binding specificity, and the mechanism of specific site recognition, according to lead researcher Carlos Bustamente.

"Molecular recognition is important not only in gene regulation, but in many other biological processes," says Kamal Shukla, Molecular Biophysics Program Director at the National Science Foundation. "It also has many applications in biotechnology. Visualizing this recognition illustrates the power of advanced biophysical techniques. SFM makes possible the characterization of many molecular assemblies that are too large to be determined by conventional X-ray crystallography and nuclear magnetic resonance techniques."

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