P53 conformational switching for selectivity may reveal a general solution for specific DNA binding

Abstract

DNA-binding proteins are integral members of the cell community, having indispensable roles in critical DNA processes such as gene expression regulation, replication, transcription, and genomic maintenance. Yet, how these critical proteins efficiently recognize their target binding sites in the vast excess of DNAwithin the genome has been perplexing. In this issue of The EMBO Journal, Petty et al (2011) provide insights into this enigma by combining structure, fluorescence anisotropy, and mutational analysis of the sequence-specific DNA-binding protein p53 to reveal a basis for discriminating between specific and non-specific DNA targets: a DNA-binding-mediated conformational switch regulates DNA off-rates independent of affinities. Besides explaining the prevalence of conformational switches in sequence-specific protein-DNA interactions, these findings could also be broadly relevant for specific DNA binding including such processes as DNA repair. © 2011 European Molecular Biology Organization.