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

7,8-Dihydro-8-oxoguanine (8-oxoG), a frequent mutagenic base modification occurring upon oxidative stress, is handled by the DNA glycosylase OGG1 when paired with cytosine, initiating the base excision repair pathway. Since 8-oxoG neither significantly impacts the DNA structure nor blocks transcription and replication, its detection requires a careful inspection of each base pair by OGG1. By monitoring this lesion search process in vitro and in living cells, we uncover a tight coordination between several conserved amino acids encircling the DNA. 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 mechanisms that enable OGG1 to maintain rapid DNA sampling kinetics while preserving specificity for 8-oxoG in the context of the chromatin architecture within the nucleus.