Speed–Specificity Trade-Offs in the Transcription Factors Search for Their Genomic Binding Sites

Transcription factors (TFs) regulate gene expression by binding DNA sequences recognized by their DNA-binding domains (DBDs). DBD-recognized motifs are short and highly abundant in genomes. The ability of TFs to bind a specific subset of motif-containing sites, and to do so rapidly upon activation, is fundamental for gene expression in all eukaryotes. Despite extensive interest, our understanding of the TF-target search process is fragmented; although binding specificity and detection speed are two facets of this same process, trade-offs between them are rarely addressed. In this opinion article, we discuss potential speed–specificity trade-offs in the context of existing models. We further discuss the recently described ‘distributed specificity’ paradigm, suggesting that intrinsically disordered regions (IDRs) promote specificity while reducing the TF-target search time.