  Strong experimental and theoretical evidence shows that transcription factors
and other specific DNA-binding proteins find their sites using a two-mode
search: alternating between 3D diffusion through the cell and 1D sliding along
the DNA. We consider the role spatial effects in the mechanism on two different
scales. First, we reconcile recent experimental findings by showing that the 3D
diffusion of the transcription factor is often local, i.e. the transcription
factor lands quite near its dissociation site. Second, we discriminate between
two types of searches: global searches and local searches. We show that these
searches differ significantly in average search time and the variability of
search time. Using experimentally measured parameter values, we also show that
1D and 3D search is not optimally balanced, leading to much larger estimates of
search time. Together, these results lead to a number of biological
implications including suggestions of how prokaryotes and eukaryotes achieve
rapid gene regulation and the relationship between the search mechanism and
noise in gene expression.
