A coordinated haptic mechanism ensures efficient DNA sampling by the 8-oxoguanine glycosylase OGG1.

7,8-Dihydro-8-oxoguanine (8-oxoG) is the most frequent base modification occurring upon oxidative stress. This highly mutagenic lesion is specifically recognized and excised by the DNA glycosylase OGG1 when paired with cytosine, initiating the base excision repair pathway. Since 8-oxoG neither significantly impacts the structure of the double helix nor blocks transcription and replication processes, its detection requires a careful inspection of each base pair by OGG1. By monitoring this lesion search process both in vitro and in living cells, we demonstrate that it involves a tight coordination between several conserved amino acids encircling the DNA helix. More specifically, we show that the N149-151 motif, on the target strand, as well as residues R154 and R204, on the opposite strand, both regulate OGG1 engagement on the DNA to ensure fast Y203-mediated base unstacking, a prerequisite for efficient 8-oxoG detection. These findings highlight the early mechanisms that enable OGG1 to maintain rapid sampling kinetics while preserving high specificity for 8-oxoG in the context of the complex architecture displayed by the DNA within the cell nucleus.