Efficient recognition of specific sites in DNA by repair proteins requires resolution of the fundamental “speed–stability paradox.” This paradox arises from the need to scan a vast genome rapidly while maintaining high accuracy in lesion detection. Classical models of protein–DNA interactions have shown that the association rate constants for site-specific complexes can approach or even exceed the diffusion limit, implying the existence of specialized mechanisms of facilitated, or accelerated, diffusion. Experimental and theoretical studies have identified several such mechanisms, including one-dimensional sliding along the DNA helix, two-dimensional diffusion over the DNA surface, intersegmental transfer, and dissociation–reassociation through hopping or jumping. These modes may operate in combination, and their relative contributions are determined by DNA conformation, structural features of the protein, and the cellular context. Particular attention has been paid to DNA glycosylases, which initiate base excision repair by locating and excising damaged bases with high efficiency and fidelity. Single-molecule studies of glycosylases such as human OGG1 and bacterial Fpg have shown that rapid sliding is often coupled with helical rotation, transient base interrogation, and conformational checkpoints that enable discrimination between damaged and undamaged bases. Disordered protein termini and specific amino acid residues may function as molecular wedges or anchors that promote lesion recognition, whereas cooperative protein–protein interactions may further facilitate target localization and catalytic turnover. Collectively, these findings indicate that DNA damage search and recognition are governed by a dynamic interplay of multidimensional diffusion, conformational probing, and interprotein cooperation, thereby ensuring both speed and precision in genome surveillance. • Efficient protein recognition of DNA sites must resolve the speed–stability paradox. • Damaged base detection arises from rearrangements within biopolymer molecules. • Protein interplay ensures both speed and precision in genome surveillance.
Lukina et al. (Tue,) studied this question.