Mechanisms of enhanced or impaired DNA target selectivity driven by protein dimerization

Successful DNA transcription demands coordination between proteins that bind DNA while simultaneously binding to one another into dimers or higher-order complexes. Measurements that report on the lifetime or occupancy of an individual protein on DNA thus represent a convolution over the protein interactions with specific DNA, nonspecific DNA, or protein partners on DNA. For some DNA-binding proteins, dimerization is considered an essential step for stable DNA association, but here we show that protein dimerization can also reduce dwell times on specific DNA targets, enhance or impair occupancy on target sequences, and spatially redistribute proteins on DNA. We use mass-action kinetic models of pairwise association reactions between proteins and DNA (specific and nonspecific) and protein dimers, along with theory and spatial stochastic simulations to isolate the role of dimerization on observed dwell times and occupancy. For proteins binding a spatially localized cluster of targets, dimerization can drive up dwell time by 1000-fold and produce high selectivity for clustered over isolated targets. However, this effect can become negligible when proteins outnumber target sequences. In contrast, for isolated DNA targets, dimerization often reduces dwell times by sequestering proteins from their target sites, in some cases thus reducing overall occupancy. The ability of these proteins to bind DNA nonspecifically and diffuse in 1D to exploit dimensional reduction is a key determinant controlling degree of enhancement, despite the presence of nucleosome barriers to 1D diffusion. By comparison with ChipSeq data, our model explains how the distribution of the GAF pioneer proteins throughout the genome is highly selective for clustered targets due to protein interactions and provides a framework to predict how even weak dimerization can redistribute or stabilize proteins on DNA.