Jon Widom, Northwestern University, Chicago, USA.

Protein-DNA Interaction
Proteins that regulate genes need to find, recognize, and bind to specific target sites on large chromosomal DNA molecules. The search process itself includes three dimensional random walks, but achieves important rate enhancements from reducing the dimensionality of the search, through one-dimensional "sliding", together with direct transfer via DNA looping. Once a regulatory protein has arrived near its target site, it must recognize the target site as distinct from the rest of the genome, and then bind to it. Specific site recognition typically includes both direct and indirect contributions. Direct recognition involves specific interactions between the regulatory protein and particular patterns of DNA atoms that are unique to one DNA sequence or another. In indirect recognition, the protein requires the DNA to strongly deform in order to bind, and senses how easily different DNA sequences accommodate this structural requirement. Many sequence-specific protein-DNA complexes include significant contributions from both direct and indirect readout. The nucleosome is an extreme example, in which sequence specificity appears to be entirely indirect. This tutorial will review what is known, and not known, about the search process itself. We will briefly review essential aspects of direct readout, which is largely well understood. We will then focus on indirect readout, which is a subject of intense current research. We will discuss new experiments that reveal an intimate connection between the sequence of a DNA molecule and its structural and dynamic properties; and a new meso-scale physical model and computational analysis that allows these properties to be predicted from the sequence alone. Finally, we will discuss how these principles allow the genome to explicitly encode its own organization into three dimensional space.

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