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 to form dimers or higher-order complexes. For proteins with numerous DNA targets throughout the genome, measurements that report on their dwell time or occupancy thus represent a convolution over a population interacting with specific DNA, nonspecific DNA, or protein partners on DNA. Dimerization is known to add contacts that can help a protein monomer to stably bind DNA. However, we show here that dimerization can also impair measured dwell times and occupancy on target sequences because the population redistributes across DNA. We combine spatial stochastic simulations of pairwise reversible reactions between proteins and DNA with mass-action kinetic models and theory to isolate the role of reversible dimerization on observed DNA dwell times, occupancy, and spatial distribution of proteins on DNA. Three key themes emerge: (i) Protein-protein interactions, in addition to protein-DNA interactions, can localize a protein to DNA, and rates of (un)binding can thus widely tune dwell times. (ii) Dimensional reduction achieved through nonspecific binding and subsequent 1D diffusion controls the order of magnitude of enhancements despite nucleosome barriers. (iii) Dimerization enhances selectivity for locally clustered targets and often impairs binding to widely spaced targets by sequestration. Compared with ChIP-seq data, our model explains how the distribution of the essential GAGA factor monomer throughout the genome is highly selective for clustered targets due to protein interactions. This model framework predicts when even weak dimerization can redistribute and stabilize proteins on DNA as a necessary part of transcription.