Base-Independent DNA Base-Excision Repair of 8‑Oxoguanine

Living organisms protect their genome from gene mutation by excising damaged DNA bases. Here, 8-oxoguanine (8OG) is one of the most abundant DNA lesions. In bacteria the base excision is catalyzed by the enzyme formamidopyrimidine-DNA- glycosylase (Fpg), for which two different orientations of 8OG binding into the active site of Fpg have been proposed: syn- and anti-conformation. Here, we present a new ribose-protonated repair mechanism for 8OG that is base-independent and can excise 8OG in both conformations. Using high-level QM/MM calculations with up to 588/573 atoms in the QM sphere, the activation barrier is computed in excellent agreement with the experimentally measured value. Since the excised base itself is not directly involved in the mechanism, this implies that lesion discrimination does not occur within the active site of the enzyme.