Mechanism of Error‐Free Bypass of the Environmental Carcinogen N‐(2‐Deoxyguanosin‐8‐yl)‐3‐aminobenzanthrone Adduct by Human DNA Polymerase

The environmental pollutant 3-nitrobenzanthrone produces bulky aminobenzanthrone (ABA) DNA adducts with both guanine and adenine nucleobases. A major product occurs at the C8 position of guanine (C8-dG-ABA). These adducts present a strong block to replicative polymerases but, remarkably, can be bypassed in a largely error-free manner by the human Y-family polymerase (hPol). Here, we report the crystal structure of a ternary PolDNAdCTP complex between a C8-dG-ABA-containing template:primer duplex and hPol. The complex was captured at the insertion stage and provides crucial insight into the mechanism of error-free bypass of this bulky lesion. Specifically, bypass involves accommodation of the ABA moiety inside a hydrophobic cleft to the side of the enzyme active site and formation of an intra-nucleotide hydrogen bond between the phosphate and ABA amino moiety, allowing the adducted guanine to form a standard Watson-Crick pair with the incoming dCTP.