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Transcription factor mobility is a determining factor in the regulation of gene expression. Here, we have studied the intranuclear dynamics of the glucocorticoid receptor (GR) by using fluorescence recovery after photobleaching and single-molecule microscopy. First, we have described the dynamic states in which the GR occurs. Second, we have analyzed the transitions between these states by using a continuous-time Markov chain model and functionally investigated these states by making specific mutations in the DNA-binding domain. This analysis revealed that the GR diffuses freely through the nucleus and, once it leaves this free diffusion state, most often enters a repetitive switching mode. In this mode it alternates between slow diffusion as a result of brief nonspecific DNA-binding events, and a state of stable binding to specific DNA target sites. This repetitive switching mechanism results in a compact search strategy that facilitates finding of DNA target sites by the GR.This article has an associated First Person interview with the first author of the paper.

Repetitive switching between DNA binding modes enables target finding by the glucocorticoid receptor